Method and device for implantation of large diameter objects in bovines

ABSTRACT

A method and device for implanting large diameter objects subcutaneously or into the peritoneal cavity of bovines employs a beveled, puncturing, but substantially non-incising trocar.

This application is a divisional of U.S. Ser. No. 08/270,196 filed Jul.1, 1994, now pending.

FIELD OF THE INVENTION

The invention relates to method and device for implantation of largediameter devices or capsules in bovines. In one aspect, the inventionrelates to a method of implantation which is effective and from whichthe bovine readily heals. In another aspect, the invention relates to adevice specifically adapted for intraperitoneal implantation in bovineswhich can be used in such a method.

SETTING OF THE INVENTION

In the field of raising cattle for dairy products and meat, it issometimes desirable for various reasons to implant a large diameterobject subcutaneously or in the intraperitoneal cavity of the bovines.For example, in preparing finishing beef cattle for slaughter, it may bedesired to insert a prolonged release device or capsule or pellet intothe intraperitoneal cavity to enhance average daily gain, body weight,carcass weight, dressing percentage and the like. As another example, inenhancing milk production in dairy cattle, it may be desirable toimplant such devices or capsules or pellets subcutaneously such asdescribed in Supplemental Exemplary Embodiment A and SupplementalExemplary Embodiment B. It may also be desirable to implant largediameter devices such as temperature monitors and other electronicinstrumentation, animal identification transponders, and the like. Manyother large diameter devices will occur to those skilled in the art.

Such devices or capsules or pellets in order to provide a suitablyprolonged release and to be readily visible after the slaughter Of theanimal may be of substantial size. However, feedlot operators andtechnicians and cattle and dairy farmers are reluctant to undertake suchtreatment with large diameter objects, although advantageous andeconomically beneficial, unless it can be accomplished readily, withoutsignificant injury to the bovine, requires minimal care, and suitablyheals. Thus, implantation of large diameter objects presents asignificant problem to animal husbandry and also to the providers oftreatments and devices for cattle.

The prior art has dealt with devices for injection of liquids into theperitoneal cavity and with trocars for relieving bloating of the rumen.The rumen is the first division of the stomach of a ruminant animal,distended into the peritoneal cavity, in which food is partly digestedbefore being regurgitated for further chewing.

The prior art has also dealt with devices for subcutaneous implantationof pellets. The pellets are generally of relatively small diameter andthe implanters generally have hide-incising tips which, if they weremade larger and came into contact with underlying tissues, would causerelatively extensive bleeding and damage. Moreover, coring of the hideand underlying flesh could result, facilitating peritonitis if suchmaterials were discharged into the peritoneal cavity, and generallyimpeding healing.

SUMMARY OF THE INVENTION

In accordance with the invention, a method is provided for implantinglarge diameter objects in the intraperitoneal cavity of bovines whichcan be accomplished readily, without significant injury to the bovine,requires minimal care after implantation, and suitably heals.

The method comprises providing a generally cylindrical large diameterobject with an outside diameter in the range of about 8 to about 15millimeters (mm). An incision is made in the hide of the left paralumbarfossa of the bovine, the incision having an orientation and length anddepth such that gaping of the resulting wound substantially does notoccur after inserting an object therethrough. A generally cylindricaltube having an external diameter of less than about 25 mm for passingthrough the opening and having an internal diameter for passing thelarge diameter objects therethrough and having a non-hide-incising tipeffective for penetrating underlying tissues and for puncturing theperitoneum and a length for extending through the incision, theunderlying tissues and into the peritoneal cavity, is inserted into theincision, and is caused to puncture and penetrate the peritoneum, andthe large diameter objects are inserted therethrough. The tube isremoved and the incision in the hide closes.

In accordance with a further aspect of the invention, there is provideda device for the subcutaneous or intraperitoneal implantation of largediameter substantially size-invariant objects into a bovine. The devicecomprises a plastic tube having an outside diameter of less than about25 mm and an inside diameter effective for passing therethrough objectshaving an outside diameter in the range of about 8 to about 15 mm. Afirst end of the tube is beveled and has a non-hide-incising tipeffective for penetrating tissues underlying an incision in the hide andfor puncturing the peritoneum. Adjacent the first end is means forreleasably retaining large diameter objects in the tube while the tubeis inserted into the incision in the bovine's hide. Adjacent the secondend is a slidable seal which can be urged to deliver the large diameterobjects within the tube past the releasing means and out of the firstend of the tube.

In accordance with another aspect of the invention there is provided adisposable administration package or article of manufacture forintraperitoneal administration of a beneficial agent to a bovine. Thearticle comprises a disposable plastic tube having a non-hide-incisingtip at a first end, the tip being effective for penetrating bovinetissues underlying an incision in the hide and being effective forpenetrating the intraperitoneal cavity of the bovine. A plastic sheathsterilely encloses a first portion of the tube adjacent a first end, thefirst portion having a length effective for extending from leftparalumbar fossa of a bovine into the intraperitoneal cavity. Retainingmeans is provided adjacent the first end for releasably retainingobjects within the tube after the sheath is removed. The tube enclosesone or more osmotically-driven pumps having an outside diameter of about8 to about 15 mm for delivery of a beneficial agent. A seal adjacent thesecond end of the tube completes sterile or low bioburden enclosure ofcontents of the tube.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention will be further understood and appreciated from thefollowing detailed description and the drawings in which:

FIG. 1 is a line drawing of the hind portion of a bovine showing atypical arrangement of left paralumbar fossa, an adjacent portion of theintraperitoneal cavity, and the rumen.

FIG. 2 is a modified FIG. 1 showing an incision made in the hide of thebovine and a device in accordance with the invention inserted into theopening and through the peritoneum into a portion of the peritonealcavity.

FIG. 3 is a schematic illustration of a device for implanting largediameter objects mounted in a gun for administering the implants, all inaccordance with the invention.

FIG. 4 illustrates the exterior appearance of a device in accordancewith the invention.

FIG. 4A is a longitudinal section along the line 4A--4A in FIG. 4.

FIG. 5 is a detail drawing showing the appearance of the obverse side ofthe tip of the device of FIG. 4.

FIG. 6 is a longitudinal section of the portion designated 6 in FIG. 3.

FIG. 7 is a detail drawing illustrating a longitudinal section throughthe tip of the invented trocar.

FIG. 8 is a detail drawing of the portion designated 8 in FIG. 4.

FIG. 9 illustrates removal of the sheath from the combined trocar andgun of FIG. 3.

FIG. 10 illustrates a longitudinal section through a seal adjacent thesecond end of an embodiment of the invented trocar.

FIG. 11 illustrates the exterior appearance of cap 102b.

FIG. 12 illustrates an axial longitudinal section along the line 12--12in FIG. 11.

FIG. 13 illustrates in detail the region identified as 13 in FIG. 12.

FIG. 14 illustrates a package in accordance with the invention.

FIG. 15 illustrates a sealed package comprising a plurality of sterilepackages in accordance with FIG. 3.

FIGS. 16-22 depict features of a preferred osmotic pump that can beimplanted using the device of the instant invention.

FIG. 23 is a graph showing passage of water by the piston of FIG. 18from the internal compartment surrounded by an impermeable first wallsection into the internal compartment surrounded by permeable secondwall section of FIG. 16.

FIG. 24 is a graph showing passage of water by the piston of FIG. 18from the internal compartment surrounded by an impermeable first wallsection into the internal compartment surrounded by permeable secondwall section of FIG. 16, excluding data ≧three standard deviations fromthe mean.

FIG. 25 is a graph depicting the real time pressure release for a sealof Multiwax X-145a wax having a thickness of 0.050 inches.

FIG. 26 is a graph showing the effect of the exit port aperture diameteron the diffusion of water using an exit passageway length of 0.100inches and specified diameter.

The invention will now be described in detail showing preferredembodiments of the invention, but is not limited thereto, but by theclaims appended hereto interpreted in accordance with law.

DETAILED DESCRIPTION OF THE INVENTION

In accordance with the invention, a method is provided for implantinglarge diameter objects in the intraperitoneal cavity of bovines whichcan be accomplished readily, without significant injury to the bovine,requires minimal care after implantation, and readily heals.

The method comprises providing a generally cylindrical size-invariantlarge diameter object with an outside diameter in the range of about 8to about 15 mm. The objects can be, for example, capsules, pellets,mechanical or osmotic pumps for delivering beneficial agents, electronicidentification devices and monitors, and the like. As used herein,size-invariant refers to an object whose diameter does not significantlyalter during implantation, for example, by crushing or otherwise. In apreferred embodiment, the objects are osmotic pumps for the deliveringof a beneficial agent such as described in Supplemental ExemplaryEmbodiment A.

The minimum outside diameter of the large diameter objects in accordancewith the invention is about 8 mm since it has been found that suchdevices can be made effective for delivering a beneficial agent over aprolonged length of time, and can be readily identified at the time ofslaughter. The maximum outside diameter in accordance with the inventionis about 15 mm since larger diameter objects require an incision in thehide of the animal greater than about 20 to 25 mm in length and it hasbeen determined that when the incision is less than this range thatsubstantial sealing of the wound occurs rapidly, often within 15 minutesor less of implantation, so that mechanical force is required to reopenthe incision, and very low incidence of injection site responses isobserved. Further the peritoneal wound also effectively heals and whenlow bioload or sterility of the device is maintained little or noperitonitis other than localized non-septic peritonitis has beenobserved. See Examples 1 and 2 below.

In accordance with an aspect of the invention, an incision is madepreferably vertically, in the hide of the left paralumbar fossa of thebovine, the incision having a length of less than about 20 to 25 mm suchthat gaping of the resulting wound does not occur after inserting anobject therethrough and the wound readily seals. Preferably the incisionis vertical relative to the ground, only in the hide, and substantiallynot in the underlying muscle layers which are more highly vascularized,thus minimizing bleeding. Controlled incision is also preferable becauseto the extent the underlying muscle tissues are incised, gaping of thewound is more likely to occur at shorter lengths of incision due tosymmetrical destruction of the underlying tissues. The incision can bemade by means known in the art such as scalpel, laser, and the like.

In accordance with the invention, large diameter substantiallysize-invariant objects are provided for intraperitoneal implantation.Such objects can be, for example, pellets or capsules of bovinesomatotropin, of estrogen, or other metabolic regulators or drugs, orelectronic devices and monitors. For example, the objects can beappropriately sized bovine somatotropin pellets as disclosed in U.S.Pat. No. 5,091,185. Alternatively and preferably, such objects can bedevices for delivering bovine somatotropin and/or estrogen at apulsatile or substantially constant rate such as described inSupplemental Exemplary Embodiment A and Supplemental ExemplaryEmbodiment B. Most preferably the objects are osmotic pumps such as aredescribed in Supplemental Exemplary Embodiment A.

In accordance with a preferred embodiment of the invention, a disposableplastic generally cylindrical tube having an external diameter of lessthan about 25 mm, for example 20 mm, for passing through the incisionand having an internal diameter for passing the large diameter objectstherethrough and having a substantially non-hide-incising tip effectivefor penetrating underlying tissues after the incision has been made andfor puncturing the peritoneum and having a length for extending throughthe incision, the underlying tissues and into the peritoneal cavity, isinserted into the incision, is caused to penetrate the underlyingtissues and to puncture and penetrate the peritoneum, and the largediameter objects are inserted therethrough. Preferably the lengthinserted into the bovine is sterile prior to use.

As used herein, plastic according to its general technical usage refersto a high polymer, usually synthetic, optionally combined with otheringredients such as curatives, fillers, reinforcing agents, colorants,plasticizers, and the like, which can be formed or molded under heat orpressure in its raw state and machined to high dimensional accuracy,trimmed and finished in its hardened state.

The puncturing non-incising tip is beveled or slanted to facilitatepassage through underlying tissues, but is substantially non-incising toreduce cutting or coring or both of the underlying tissues. Use of abeveled, mostly non-incising tip to pass through the muscle layersresults in tearing, rather than incision, of the muscles; and damage tovascular structure and bleeding is reduced and healing facilitatedbecause of quicker clotting and other factors. Preferably the bevel isless than 35° since 40° and 45° bevels cannot efficiently be urgedthrough underlying tissues. 30° is much better than 35°, while 25° isonly marginally better than 30°. To minimize length of the trocar it ispreferred that the bevel be in the range of about 25° to about 35°relative to the horizontal axis.

The peritoneum is the serous membrane lining of the abdominal walls(parietal peritoneum) and investing the viscera (visceral peritoneum).The parietal peritoneum is the membrane which lines the abdominal andpelvic walls and the undersurface of the diaphragm. The visceralperitoneum is the membrane reflected at various places over the viscera,forming a complete covering for the stomach, spleen, liver, ascendingportion of the duodenum, jejunum, ileum, transverse colon, sigmoidflexure, upper end of the rectum, uterus, and ovaries; it also partiallycovers the descending and transverse portions of the duodenum, thececum, ascending and descending colon, the middle part of the rectum,the posterior wall of the bladder, and the upper portion the vagina. Theperitoneum serves to hold the viscera in position by folds, some ofwhich form the mesenteries, which connect portions of the intestine withthe posterior abdominal wall; others form the omenta, folds attached tothe stomach, and still others, the ligaments of the liver, spleen,stomach, kidneys, bladder, and uterus. The space between the parietaland visceral peritoneums is the peritoneal cavity, which consists of thepelvic peritoneal cavity below and general peritoneal cavity above. Thegeneral peritoneal cavity communicates by the foramen of Winslow withthe cavity of the great omentum, which is also known as the lesserperitoneal cavity. As used herein, intraperitoneal cavity includes anyof the pelvic peritoneal cavity, the general peritoneal cavity, and thelesser peritoneal cavity. More preferably, the implant is inserted intothe lesser peritoneal cavity.

It has been discovered that access to the peritoneal cavity in bovinesis best gained through the left paralumbar fossa in bovines which havebeen fasting or feed-restricted as discussed below. Initially, it wasthought that insertion through the right paralumbar fossa would be thepreferred side, as the rumen is positioned adjacent the left paralumbarfossa, and it was desired to avoid the possibility of damage to therumen. However, the kidneys and associated kidney fat are asymmetricallydistributed in the bovine toward the right side of the body andinterfere with access to the peritoneal cavity on that side and furtherrequire a longer tube for implantation to assure that the implants aredischarged into the intraperitoneal cavity and not into kidney fat orkidney where ineffective release or damage to the animal would occur.For this reason access to the intraperitoneal cavity in accordance withthe invented method is accomplished through the left paralumbar fossa.

Referring to FIG. 1, the left paralumbar fossa is a generally triangulararea 42 of about 6-8 inches diameter on bovine 40 between the hip bone44 and the last rib and below the loin area on the left side. Tissue andhide depth here is typically about 0.5 to 2.0", hence tubes used forintraperitoneal implantation can be generally on the order of 1 to 5inches or longer. The insertion depth of the tube needs to be greaterthan the actual thickness of the paralumbar region due to the potentialfor stretching of the peritoneal lining. As indicated above, the onlyinternal organ presenting a risk of injury via the left paralumbar fossais the rumen 46, provided the trocar is not pointed upward toward thekidney.

Damage to the rumen can be eliminated or reduced by applying theinvented method to animals whose rumen is not too much distended intothe target peritoneal cavity, for example, to fasting or feed-restrictedanimals. Preferably animals treated in accordance with the inventedmethod have been fasting or feed restricted (reduced feed or water-only)for 6 to 24 hours, most preferably about 10 to 18 hours prior toadministration since it has been observed that the rumen is typicallyflaccid or at least not typically distended into the implantation areaat this time facilitating avoidance of injury.

After implantation, the specified incision in the hide (See referencenumeral 46 is FIG. 1), which is preferably vertical to facilitateclosure and to prevent pooling of blood and fluids during closure, isoften already undergoing sealing and closure in 15 minutes to 1 hour sothat force would have to be applied to reopen the incision.Investigation of the length of incision has shown that so long as thelength is less than about 25 mm, more preferably, less than about 20 mm,this rapid sealing phenomenon is observed. Likewise, examination ofbovines following slaughter has shown that they are overwhelmingly freeof signs of peritonitis other than localized non-septic peritonitis.

The invention can be further illustrated by reference to the Figures,particularly FIGS. 1 and 2, wherein reference numeral 40 indicates theleft paralumbar region of a bovine 42, reference numeral 44 indicatesthe targeted portion of the peritoneal cavity, 46 indicates the adjacentrumen, and 48 illustrates a vertical incision in the left paralumbarfossa. Referring now to FIG. 2, FIG. 2 further shows administration gun140 having device 102 mounted therein inserted into the targetedperitoneal cavity 44.

Thus, in accordance with the invention, a method has been provided forimplanting large diameter objects in the intraperitoneal cavity ofbovines which can be accomplished readily, without significant injury tothe bovine, requires minimal care after implantation, and rapidly heals.

In accordance with another aspect of the invention, there is provided adevice for the intraperitoneal implantation of large diametersize-invariant objects into a bovine.

The device preferably comprises a plastic tube having an outsidediameter of less than about 25 mm, preferably less than about 20 mm, andan inside diameter for passing therethrough large diametersize-invariant objects having an outside diameter in the range of about8 to about 15 mm. In a first portion of its length which can be sized toextend from hide to intraperitoneal cavity in a bovine, the outersurface of the first portion is preferably sterile prior to use. A firstend of the tube adjacent the first portion is beveled and has apuncturing but substantially non-hide-incising tip having a hardness andstiffness effective for puncturing the peritoneum. Adjacent the firstend is means for releasably retaining the large diameter objects in thetube while the tube is inserted into an incision in the bovine's hide.Adjacent the second end is a slidable seal which can be urged to deliverthe large diameter objects within the tube past the releasing means andout of the first end.

Referring now to FIG. 3, FIG. 3 illustrates administration gun 140having package 102 mounted therein. Gun 140 has push rod 142 which canbe used to deliver implants 128 as hereinafter described.

Referring now to FIG. 4, package 102 comprises trocar 102a and itscontents hereinafter described and sheath 102b. Reference numeral 102aindicates a generally cylindrical plastic tube of unitary constructionhaving an outside diameter of less than about 25 mm and an insidediameter capable of receiving generally cylindrical size-invariantobjects having an outside diameter in the range of about 8 mm to about15 mm.

As illustrated, the generally cylindrical plastic tube 102a may overallslightly taper distally, as illustrated, from right to left, sufficientto facilitate molding and mold-release of the device. The sidewallthickness of the device can also narrow distally as best illustrated inFIG. 13. The device is of a moldable or machinable plastic, preferably amoldable plastic having a hardness such that a tip 104 can be molded ormachined tip effective for puncturing the peritoneal membrane but isotherwise substantially non-incising. Alternatively, a puncturing tipmay be attached to the tube after construction or during molding. Thegenerally cylindrical tube can be made of any non-toxic plastic whichhas appropriate strength, moldability, stiffness and, optionally, lowmoisture transmission rate. Thus the generally cylindrical tube can bepolycarbonate, polyvinylchloride, acrylonitrile-butadiene-styrene (ABS),and the like. ABS is preferred because of its strength, moldability,stiffness and low moisture transmission rate, for example, Lustran® ABSavailable from Monsanto Company, St. Louis, Mo. The trocar can have aslight taper on both the interior and exterior sidewall to facilitatemolding. Preferably, however, there is no taper of the interior diameterwhere seal 134 (See FIG. 4A) is seated adjacent the preferably chamferedsecond end as illustrated by reference numeral 118a; nor preferably isthere taper of the exterior diameter in portion 116a, adjacent shoulder120, where the sheath seals to the tube.

Device 102 comprises a first end 106 and a second end 108. First end 106has a tip 104 which can be formed by double-beveling the tip of thetube, as illustrated. Generally, as discussed above, the primary bevel110 is in the range of about 20 to 35 degrees, while the secondary bevel112 (See FIG. 8) is in the range of 30 to 40 degrees measured as theangle between the bevel and a plane perpendicular to the longitudinalaxis of the trocar, for example 34 degrees. Preferably, as illustrated,the bevels are selected to minimize the length of device 102 whileproviding a suitable puncturing tip. The inside surface or heel of tube102, as illustrated at 115 in FIG. 6, can be rounded slightly tominimize roughness and the tendency to scrape and carry flesh, hair, andthe like as device 102 is inserted into the flesh of an animal. Thelower surface of the tip, as best illustrated by reference numeral 150in FIG. 7, can be angled, for example, at about 5° relative to alongitudinal axis, to reduce thickness of the puncturing tip.

As illustrated, device 102 consists of first and second body portions116 and 118 respectively, having substantially the same or slightlydistally tapering inside diameters and different outside diametersforming a shoulder 120 therebetween. Shoulder 120 can be used to receiveand seat the sheath, discussed below, and also to gauge or limitinsertion of device 102 into a bovine after the sheath is removed.Alternatively, the outside diameters can be the same. The length of thefirst portion from shoulder 120 to tip 104 is preferably sufficient toextend from the hide to the peritoneum of a bovine at the leftparalumbar fossa. Thus, this length can be on the order of 1 to 5inches. 4 inches has been found to be effective for puncturing theperitoneum even with a relatively inefficient tip. With a more efficienttip a lesser length of the first portion will be advantageous. Longerlengths can also be used.

As illustrated, a closed cap or sheath 102b having a coaxial tubiformspacer 124 molded in the tip thereof and having a generally cylindricalwall 126 is inserted on the first portion 116 maintaining the outersurface sterile before use. Spacer 124 has a length for ensuring thatimplants 128 do not rest on protuberance 130 while cap 102b is on device102. As illustrated, molded sealing rings or annular ridges 127 of wall126 (See FIGS. 12 and 13) rest against shoulder 120. Cap 102b ispreferably constructed of an elastomeric material such that the annularrings will snuggly but removably engage portion 116a of trocar 102a.Sheath 102b can be molded of any plastic which has suitable moldabilityand pliability to allow for maintaining a sterility and/or moisture sealwhen installed on device 102. Optionally, the plastic can have a lowmoisture transmission rate. A preferred plastic is a polypropylene, forexample, one having the characteristics of Himont PD626 available fromHimont, Wilmington, Del. The length of the sheath is determined by thelength of the device 102 which will be inserted into contact with bovinetissues, i.e., the combined length of 116a and 116b. The sheath can beslightly tapered so as to facilitate mold-release and to avoid a vacuumwhen sheath 102b is removed from device 102.

According to the invention, means is provided adjacent the tip forreleasably retaining implants 128 within device 102 when the cap isremoved and device 102 is held vertically. Many suitable means willoccur to those skilled in the art. Preferably the means is of a typewhich can be molded and is made of the same material as device 102 sincethis simplifies manufacture. In the illustrated embodiment, the meanscomprises a bump or convex protrusion 130 (See FIGS. 4, 6, 7, and 8)which is molded on the interior sidewall of portion 116b on a flexiblestrip 131 (See FIGS. 5 and 8) bounded by longitudinal slits 132 passingthrough the sidewall. When cap 102b (See FIG. 9) is removed and implant128 is urged, as hereinafter described, by push rod 142 toward tip 102,the pressure exerted by the implant 128 on protuberance 130 will causestrip 133 (See FIG. 6) to bow outwardly permitting passage of implants128. When cap 102b is in place, for example during shipping andhandling, spacer 124 maintains the implants away from protuberance 130.Thus cap 102b, spacer 124, and the retaining means cooperate to providean effective, moldable device.

In the illustrated embodiment of FIG. 3, second portion 118, togetherwith first portion 116, and cap 102b constitute device 102. The combinedlength of device 102 is determined by the length of portion 116 whichwill traverse the bovine from hide to peritoneal cavity and by the totallength required for mounting in gun 140 and for enclosing a desirednumber of implants 128. Preferably, the number of implants 128 is anumber that will be implanted in one bovine during one administration.This number may be 1, 2, 3, or more.

Adjacent the second end of device 102 is a seal 134 for sealing (bestseen in FIGS. 4A and 10) and, in cooperation with cap 102b, formaintaining sterility of the interior of device 102. After insertion ofseal 134 the tube 102 can be heat treated adjacent the second end toprovide a stop ridge (not illustrated) holding seal 134 within tube 102.Preferably the seal is a molded plug comprising bumper 136, first andsecond side wall engaging members 138 and body 140. Preferably all partsare generally cylindrical but may be of different shapes effective fortheir respective purposes as will be apparent to those skilled in theart. The seal 134 preferably includes a generally cylindrical,preferably slightly frustoconical well 142 optionally radiused at itsproximal end and narrowing distally therein, for engaging and beingengaged by rod 142 to urge implants 128 past protuberance 130 and out ofthe first end 106 of device 102. The seal will engage rod 142 (See FIG.5) which will preferably have a length and/or range of travel such thatseal 134 cannot be expelled from the first end of device 102 during use.Preferably the point of contact between the rod and the piston is pastthe center point of the piston to limit the tendency for sealing edgesto be deviated as the seal is advanced. Bumper or spacer 136 has adiameter less than the smallest diameter adjacent protrusion 130 and alength sufficient to ensure that implants 128 can be urged beyond apoint of possible engagement with protrusion 130.

Seal 134 can preferably be molded from any suitable plastic or rubbersuch as a thermoplastic elastomer having suitable sealing and deformingcharacteristics, for example, the ability to produce a sterile andoptionally a moisture seal along a device having a slight taper.Particularly preferred is Santoprene® 271-55 brand thermoplasticelastomer, available from Monsanto Company St. Louis, Mo., which isdeformable but noncompressable under conditions of use, and has theability to produce both sterility and moisture seals and to compensatefor sidewall irregularities and taper. Other seals, such as seals usingO-rings or fabricated of other materials can also be used.

Referring now to FIGS. 4, 5, 6, 7 and 8, these Figures illustrate thepositioning of strip 133, bounded by slits 131, and having protuberance130 thereon, in a preferred embodiment of the device. As illustrated,this type of retaining means, which can be included in a mold for device102, is positioned on the side of tube 102 having the greatest length.In this way, it is insured that slits 131 are adjacent to but do notopen onto tip 104 where the openings could snag tissue and carry hairand other contaminants into the bovine. As best illustrated in FIGS. 4,6 and 8, protuberance 130 is preferably positioned opposite or counterto the shortest length of tube 102. In this way implants 128 aremaintained in the sterile interior environment of tube 102 until use,and the overall length of 102 can be kept to a minimum. Other retainingmeans are known to those skilled in the art and may be used such as, forexample, those disclosed in U.S. Pat. Nos. 2,587,364 incorporated hereinby reference, O-rings, and the like.

Referring again to FIGS. 3 and 9, these Figures illustrate a device 102mounted in a gun 140 having a push rod 142. Such devices are well-knownin general and it suffices to the person skilled in the art to point outthat gun 140, adapted for device 102, should firmly grasp device 102 insuch a way that cap 102b can be removed (See FIG. 9) after insertion inthe gun and to minimize wobble during implantation. Further, push rod142 should have a length and/or range of travel such that seal 134 ofdevice 102 cannot be expelled from first end 106.

Referring now to FIG. 14, this Figure illustrates a package 102 inaccordance with the invention comprising body 102a and closed sheath102b and containing between spacer 124 and seal 134 two implants 128,such as, for example, bovine somatotropin implants described inSupplemental Exemplary Embodiment A. Conditions of manufacture andloading are such that implants 128, and the interior and exteriorsurfaces of device 102 are preferably of low bioload and more preferablysterile. It is also envisioned that device 102 can be constructed ofmaterials which are substantially impermeable to water since, asdescribed in Supplemental Exemplary Embodiment A, the osmotic implantsmay include salt tablets whose exposure to moisture prior to use wouldresult in variable performance at startup. Alternatively, one or aplurality of devices 102 could be packaged in a water-impermeablematerial, such as foil 160, as illustrated in FIG. 15.

EXAMPLE 1

This example illustrates the significance of the incision in the hidebeing vertical and approximately 25, or 20 mm, in length or less.

Cattle were intraperitoneally implanted using a 12.6 mm outside diametermetal trocar inserted through an incision approximately 18-20 mm inlength and vertical relative to the ground. On occasion animals havebeen checked after an incision was made. The time lapse would vary fromapproximately 10-60 minutes. In all instances the incision hadcompletely closed and required that physical force be utilized tore-open the initial incision for trocar insertion. During implantationsan effort is made to keep incisions less than approximately 25 mm inlength and not to cut the muscle layers beneath. It has been observedthat when incisions are greater than 25 mm or if the muscle layers arecut with a scalpel that the incision has the propensity to gap openafter the trocar has been removed.

Histological examination has been performed on the scar left afterimplantation at 21 and 40 days post implantation. At 21 days, the lesionresembles a capital "I". The transverse upper portion of the "I" liesdirectly beneath the epidermis and extends laterally in each directionfor approximately 1 mm. It consists of a dense wide band of highlycellular collagen, primarily fibroblasts. Occasional small pockets ofinflammatory cells such as polymorphs and lymphocytes do not exceed adozen or so cells. The inflammatory portion of the reaction period iswell passed. The overlying epidermis is normal. The vertical portion ofthe "I" passes through the subcutaneous musculature in the form ofnearly mature collagen containing occasional penetrating new vessels.Beneath the musculature the "I" extends outward as a web of similarlyalmost mature collagen.

At 40 days the epidermis is normal and intact. The only evident lesionconsists of a narrow finger of mature collagen extending from thesubcutis through musculature.

The epidermis was intact and normal in all animals indicating the siteswould be difficult to detect grossly. Collagenous scar tissues wasnormal and had very limited numbers of inflammatory cells. Thecollagenous tissue still distinctly contained fibroblasts at 21 days andlesser numbers at 40 days indicating that the final shrinkage, as seenin mature scar tissue, was in progress.

EXAMPLE 2

This example illustrates that use of a low-bioburden device having anoutside diameter of 25, or 20 mm, or less, does not result significantlyin peritonitis in bovines, other than in localized non-septicperitonitis.

A series of trials were conducted with stainless steel trocars forinsertion of non-sterile, low-bioburden 5, 8 and 10 mm osmotic implantsdispensing solutions of bovine somatotropin (bST).

In the first set of trials, 5 mm osmotic implants dispensing bST at arate of about 2 to 3 mg/d were implanted into the peritoneal cavity of902 cattle. The trocar had an outside diameter of 7.1 mm and a maximuminsertion length of about 9 cm. In the case of 672 of these animals, theanimals received a second intraperitoneal implantation 42 days prior toslaughter; while the remaining 230 cattle received only oneintraperitoneal implantation 42 days prior to slaughter. At slaughterthere was a 3-5% incidence of localized non-septic peritonitis observedby the USDA Inspector-in-Charge; however implants were difficult torecover, in part due to their small size (5 mm) and to their lack ofcolor (clear). No septic peritonitis was observed.

In the second set of trials 953 cattle were implanted intraperitoneallywith non-sterile low-bioburden 8 mm, blue osmotic implants dispensingbST at a rate of about 6 to 9 mg/d. The trocar had an outside diameterof about 9.6 mm and a maximum insertion length of about 10 cm. Thecattle were slaughtered about 90 days post-implantation. These implantswere easier to recover and the incidence of localized non-septicperitonitis was comparable to that observed with the 5 mm osmoticimplants. No septic peritonitis was observed.

In a third set of trials 1153 cattle were implanted with non-sterile 10mm, blue, osmotic implants dispensing bST at a rate of about 6 to 10mg/d. The trocar used for implantation had an outside diameter of about12.6 mm and a maximum insertion length of 10 cm. The cattle wereslaughtered 120 to 140 days post-implantation. In two of these trials,each with approximately 288 implanted cattle, the non-sterile implantshad a relatively high bioburden and the incidence of adhesions betweenthe parietal peritoneum and the visceral peritoneum and the incidence oflocalized peritonitis with a more severe appearance affecting largerareas of the peritoneum cavity was observed to have increased. Theincreased bioburden indicates the desirability of sterile or at leastlow bioburden implants to avoid higher levels of adhesions and increasedseverity of localized peritonitis. In subsequent trials with lowbioburden 10 mm implants it has been observed this more severe form oflocalized peritonitis and the severity of adhesions has been reduced.

This Example illustrates that peritoneal implantation of low-bioburdenimplants reduces adhesions and does not result significantly inperitonitis in bovines other than in localized non-septic peritonitis.Use of sterile implants is expected to further decrease adhesions andfurther reduce the likelihood of septic peritonitis.

EXAMPLE 3

This example illustrates manufacture and assembly of the inventeddevice. Device 102 is molded out of an acrylonitrile-butadiene-styrene(ABS)(Lustran® 248 brand ABS available from Monsanto Company, St. Louis,Mo.) plastic with a white or a gray colorant added for appearance and toserve as a light barrier. The device has an overall length of 8.97" fromthe tip of the bevel to end of the device that is inserted into a gunfor delivery.

The bevel has an approximately 30° angle and has one bevel of 34° and asecond bevel of 5°. The tip of the bevel has been given a sharp point tofacilitate penetrating the peritoneum, however, the heel of the bevel isdulled or rounded to eliminate coring.

Internal diameter at the bevel is 0.424" and is 0.48" at the end inwhich the seal resides during storage, thus producing a taper tofacilitate molding. In the area in which the seal resides there is notaper to assure a seal between the device sidewall and thesidewall-engaging portions of the seal while the device in storage. Atthe seal end of the device a chamfer (See FIG. 4A) facilitates loadingof the implants and the seal.

At the end adjacent the beveled tip a retaining system incorporates aprotuberance between two longitudinal slits 0.02" wide by 1.0" long. Theprotuberance begins to rise 0.66" from the tip of the device and is0.021" above the inner diameter wall, thus reducing the opening from0.424" to 0.407". The protuberance has a radius of 0.25" as the implantbegins to be discharged over the protuberance and a radius of 0.40" asit passes from the protuberance. The first radius retains the implantand the second radius facilitates ejecting the part from molding. Theretaining system incorporates the protuberance height and ability toflex via the two longitudinal slits. Hence, the implant in this examplehas an outer diameter of 0.41" and is retained until the implant isexpelled past the protuberance causing approximately 0.003" deflectionin the protuberance without causing damage to the exterior of theimplant.

The outer diameter of the device consists of two different diameters.The bevel end is 3.97", the proximal 0.5 inch is not tapered, and willmaintain a 0.56" outer diameter for providing a seal surface when thesheath is applied. This end will be covered by the sheath and willremain sterile until the time of use. The second diameter is 5.0" inlength and the outside diameter is increased to 0.68" at the shoulderand is tapered to 0.77" at the second end. However, the last inch has notaper to facilitate mounting in the administration gun. An indicatingmark is added to the outer diameter to show orientation of the bevel tothe user.

Polypropylene (Himont PD626 available from Himont, Wilmington Del.) isused to mold the sheath and may or may not have a colorant added. Thesheath covers the entire area that is to be inserted into the animal atthe time of use. Total length of the sheath is 4.28" long and theoutside diameter range from 0.61" at the closed end 0.68" at the openend. In the inside at the closed end is a protruding tubiform spacerlong enough to keep the implant off of the protuberance during filling,shipping and storage.

In respect of the sheath, there are two proximal similar annular ringswhich rise 0.019" above the internal diameter of 0.6". Thus, a seal willbe made between the trocar's outside diameters, of 0.561" and the insidediameter 0.558" of the sheath's sealing rings. A balance between thesterility seal and the removal force of the sheath is accomplished bythe annular rings.

The seal is injection molded using Monsanto Santoprene and is 0.811" inlength. There are two sidewall-engaging sealing rings with an outerdiameter of 0.490" and which are 0.076" wide. The distal or front faceof the seal has an extrusion or bumper of 0.273" long by 0.25 diameterthat will insure that all implants have been pushed past protuberance130 when the push rod has passed through its preferred range of motion.The seal has a hollow in its proximal end to accept a push rod of anadministration gun to facilitate the seal's trueness as it travels downthe interior of the device.

EXAMPLE 4

This example illustrates the invented method of the invention. The leftparalumbar fossa is cleaned of debris, alternatively hair clipped, and a20 mm vertical incision is made to a depth required to pierce the hide(about 7-10 mm). The slit is placed preferentially in the exact centerof the fossa, but may also be to areas caudal to this site. A disposabletrocar is inserted through the slit, with the primary direction beingperpendicular to the skin. Inclining the trocar during insertion is notrecommended due to the possibility of injury to the loin area and/orpossible implantation into kidney fat. However, the trocar can be tiltedonce insertion is completed. A distinctive feel and/or sound cansometimes be detected by experienced technicians when the peritoneallining yields to the trocar tip. The implants contained in the trocarare discharged to the peritoneal cavity and the trocar is withdrawn. Thewound is permitted to heal with no additional attention or an antisepticis applied to the surface of the wound.

SUPPLEMENTAL EXEMPLARY EMBODIMENT A Osmotic Pump for Use With theInvention

In the following discussion, like reference numerals refer to likeelements in the figures.

FIG. 16 depicts in opened view one embodiment of a delivery device thatmay be used in accordance with the present invention. Delivery system 10of FIG. 16 comprises a housing 11 formed of a wall 12, which wall 12comprises a first wall section 12a and a second wall section 12b. Wall12, comprising first wall section 12a and second wall section 12b,surrounds and defines an internal compartment 18. Delivery system 10 hasat least one exit passageway 13 for delivering a beneficial agent 7formulation from delivery system 10, the inlet of which is in contactwith beneficial agent during storage and use. Optionally, the exitpassageway can be occluded with a material like that in seal 30,discussed below, that gets discharged, leaches or erodes during the timeof use. In FIG. 16, delivery system 10 comprises a dome-shaped rear end8 and a flattened lead end 9. In embodiments not shown, delivery system10 can be manufactured with a pair of rounded or flat ends 8 and 9. Theterm "lead end", as used herein, generally denotes the end from whichbeneficial agent 7 is released from the system. In use, either the leadend or the rear end may be implanted first.

Wall section 12a may be in the form of an tubular member having a firstand a second open ends 32 and 34, respectively. In this particularembodiment, an enclosure means 36 is positioned on first wall section12a at its lead end 9. In this particular embodiment, the enclosuremeans is in the form of an end cap 38. The wall section 12a and end cap38 together form passageway 13, seal 30 and surround that portion ofinternal compartment 18 that contains a beneficial agent 7 formulation.

Referring now to FIG. 16, wall section 12b has a first or open end 40and a second or enclosed end 42, the enclosed end at end 8 and the openend distant therefrom. Open end 40 defines and forms receiving means 19.Receiving means 19, having a first buttress 44 and second buttress 46,is received within enclosing means 20 of first wall section 12a. Firstbuttress 44 can be formed by providing the enclosing means 20 of thefirst wall section 12a with a first interior surface portion 48 having afirst inner or bore diameter and a second interior surface portion 50having a second inner or bore diameter, so that the internal buttress orinterior annular ledge 44 is formed or defined where the first andsecond interior surface portions of wall section 12a meet.

Formed on the outer surface 52 of the wall section 12b is the secondbuttress 46. Second buttress 46 is positioned to abut with the secondopen end 34 of the first wall section 12a when the enclosing means 20 ofthe wall section 12a abuts with the first buttress 44. As a result, thesecond buttress 46 in combination with the first buttress 44 forms adouble butt joint to mate the wall sections 12a and 12b for a strongjoint while minimizing the external discontinuities or surface frictionof the implant device and providing a smooth transition between thefirst and second wall sections. In this particular embodiment, theportion of the second wall section 12b inserted within the first wallsection 12a has the same thickness as that portion outside the firstwall section. In addition, as a result of this construction, the insidesurface of the first and second wall sections facilitates the travel ofthe piston along the formed smooth continuous interior surface.

As best shown in FIG. 20, the buttress 46 includes a buttress engagingsurface 54 for abutting with the first wall section 12a and an exterioror contoured surface 56 to smooth the transition from the exteriorsurface of the first wall section 12a to the exterior surface of thesecond wall section 12b. In the illustrated embodiment, when viewed incross-section, has a generally s-shape. The contoured surface 56includes a non-tapered annular portion 57, an annular convex portion 58and a concave annular portion 60. As a result, the buttress 46 extendssmoothly radially outward from the exterior surface of the second wallsection to the exterior surface diameter of the first wall section,smoothing the transition between sections of the device having differentouter diameters.

Wall section 12b surrounds that portion of internal compartment area 18that contains a means 25 for expanding and for occupying space incompartment 18 for delivery of a beneficial agent formulation fromdelivery of a beneficial agent formulation from delivery system 10. Thethickness and the surface area of the second wall section 12b contributeto the rate of passage of fluid through the membrane second wallsection. In the preferred embodiment the second wall section ispreferably formed in one piece from the water permeable material in theform of a membrane cup 12b, about 1.442 inches long, and inner diameterof about 0.288 inches. The second wall section 12b has an outer diameterof about 0.365 inches at the receiving end 19 and about 0.378 inches atthe portion not inserted within first wall section 12a. A membrane cupof substantially these dimensions provides a desired fluid flow ratethrough the comprising the second wall section of about 10-15 mg H₂O/day and more particularly about 12-14 mg H₂ O/day into contact withthe expanding means 25 therein. The two wall sections, sections 12a and12b, at receiving means 19 and enclosing means 20 are close in size.Wall section 12a and wall section 12b can be telescoped completely untilhalted by buttresses 44 or 46 into a closed and continuous internalwalled position. In the illustrated embodiment, optionally, optionally,a plurality of longitudinal ribs 66 formed upon the outer surface of thesecond wall section on the lead end or side of the engaging wall 54,space apart the first and second wall sections to define and formadhesive receiving cavities 68 between the first and second wallsections and in between the longitudinal ridges. Optionally, the wallsections 12a and 12b can be held together by heat fusion, by anadhesive, or the like. Preferably the adhesive is a cyanoacrylateadhesive having a low-enough viscosity to wick into the joint and form asecure bond. A cyanoacrylate adhesive having the same qualities andcharacteristics as that sold by Permabond of National Starch andChemical Company under the brand name Permabond USP Grade 701 Adhesiveis sufficient. Buttresses 44 and 46 ensure that the juncture of 12a and12b are smoothly and precisely joined in mated contact withoutdiscontinuities which would facilitate encapsulation of device 10.

Referring again to now to FIG. 16, there is shown, as discussed in moredetail with regards to FIG. 18, an embodiment of the mating end cap 38,adapting the end cap for ultrasonic welding to the first wall section12a; and maintaining the exit passageway 13 in contact with thebeneficial agent 7, while minimizing the dilution and/or degradation ofthe beneficial agent by adjacent body fluids present at the environmentof use 41.

The end cap 38 is especifically beneficial when delivering fluidsensitive materials, protecting the material to be delivered before andafter activation of the device. The exit port 13 is sized in diameterand length to provide a specific superficial formulation flow rate toeliminate dilution of the formulation by external fluids. The internalseal 30 provides point of use readiness without having to reopen thedevice, provides for a long term stability seal, protects formulation atstart-up and has consistent rupture pressure to provide consistentstartup. The end cap 38 also provides a headspace 112 forward of theformulation that acts to minimize internal pressure from thermalexpansion of formulations while allowing the exit port 13 maintaincontact with the formulation through all phases of the pump operation.The use of an end cap also facilitates automated Ultrasonic welding ofthe cap by protecting formulations during the welding process as aresult of a melt sink aspect of the endcap.

As best shown in FIG. 17, end cap 38 includes a first end cap side 70, asecond end cap side 72 and an exit passageway 13 extending from theexternal environment 41 into internal chamber 18 and contactingformulation 7. Exit passageway 13 is designed for an adequateformulation flow rate, driven by fluid swellable driving member 25 and apartition member 27 including piston 29 to prevent dilution of theformulation in chamber 18 by the inflow of fluids from externalenvironment 41. Exit passageway 13 is also maintains the pressure dropfor a given rate of release of the formulation from device 10. Exitpassageway 13 is preferably designed so that the rate of outflow offormulation exceeds the rate at which fluids from the externalenvironment can diffuse inwards. The length of the exit passagewayprovides a means for compensating for slight variations in the efflux oroutward flow rate of the beneficial agent. First side 70 includes anexternal face 80, the external face generally defining a planesubstantially perpendicular to the longitudinal axis of the end cap 38.The communicating passageway 78 has a generally frustro-conically shapedcontoured interior annular surface portion 79, smoothly joining thelarger diametered first exit aperture 74 with smaller diameteredcommunicating passageway 78 and second exit aperture 74.

Along its outer edge, the external face 80 joins with an annularconcentric rounded portion 82 for rounding off the edges of the device.

As best shown in FIG. 18, second side 72 of end cap 38 also includes amating portion 86 for engaging or mating with the first wall section12a, adapted for ultrasonic welding. The mating portion 86 includes anannular mating surface 88 on the second side 72 for engaging with thefirst wall section 12a, and a tenon 90 extending outward therefromtowards the first wall section 12a.

As earlier described, first wall section 12a includes first open end 32.The open end 32 has an engaging surface portion 100 for engaging withthe end cap 38. This surface or open end 100 defines a mortise 102 forreceipt of the tenon 90 extending outward from the mating surface 88 ofthe end cap 38. In one particular embodiment, the mortise is defined bya first mortise wall 104, a second mortise wall 106 and a mortise bottomwall 108.

Referring again to FIG. 17, it can be seen that end cap 38 is adaptedwith an inward extending portion 110 which defines a headspace 112between wall 12a and end cap 38. Headspace 112 remains untilled withformulation 7 after chamber 18 is filled with beneficial agentformulation 7. In this way, regardless of the orientation of device 10,beneficial agent formulation is in contact with seal 30 or with exitpassageway 13 and entrance of fluid into chamber 18 from externalenvironment 41 is inhibited. The air confined within the head space 112also allows for differential expansion of beneficial agent and plasticwithin the interior chamber 18.

As best shown in FIG. 19, second side 72 of end cap 38 also includes anextension 114 for sealing the exit passageway 13 and maintaining theexit passageway in contact with the beneficial agent 7 disposed within aportion of the internal chamber 18. The extension 114 includes agenerally cylindrical portion 116, extending outward and integral withthe annular mating portion 86 such that when the end cap 38 is matingwith the first wall section 12a. The extension portion 114 at itsterminal portion 118 includes an end cap apex 120. Apex 120 includes ordefines therein a depot 122 for receipt of a sealant. A slopingcontoured surface 124 extends and connects the annular mating surface 80with the depot 122. In one embodiment, the sloping surface 124 isgenerally s-shaped in cross-section and includes a first concave annularportion 126, a second concave annular portion 128, and a convex annularportion 130 forming a generally s-shaped surface in cross-section. Inone preferred embodiment, the first concave annular portion 126 has aslope generally defined by a radius of about 0.029 inches from a center0.125 inches radially outward from the central longitudinal axis and0.083 inches along the central longitudinal axis from the apex 120 onsecond side 72. The second concave annular portion 128, integral withand extending radially inward from the first concave annular portion126, joins with the convex annular portion 130, and has a slopegenerally defined by a radius of about 0.125 inches from a center at0.200 inches radially outward from the central longitudinal axis and0.026 inches along the central longitudinal axis from the apex 120 onthe second side 72. The convex apex portion 130.

Depot 122 is comprised of the apex 120 defining a depot bore 132, forreceipt of the sealant 30, the depot bore in fluid communication withthe interior chamber 18 and the exit passageway 13.

In the handling and operation of the device, the relationship betweenheadspace 112, depot 122 and exit passageway 13 plays a significantrole. Headspace 112 permits contraction and expansion of the formulation7 in device 10 during shipping and handling and also provides for thebuildup of pressure in device 10 after implantation into an animal.Headspace 112 insures that any air left in the formulation is not in theformulation where it can form a bubble adjacent to exit passageway 13but is confined to head space 112. If a bubble were permitted to formadjacent exit passageway 13, then when pressure built up sufficient toexpel the plug in depot 122, an inflow of fluid from the externalenvironment could dilute the formulation and the rate of delivery offormulation from device 10. In filling the device, heat treatment afterfilling assists in "setting" the formulation, locking the air bubbleinto place in headspace 112 where it will not affect initial operationof device 10.

FIG. 21 illustrates in greater detail piston 29 of FIG. 16. Piston 29 isan elastomeric piston generally cylindrical in shape which incorporatesfirst and second deformable seals 140 and 142. Piston 29 provides a highinterference seal with minimum lateral force applied to the device wallwhich would impede longitudinal travel of the piston. The deformableseals 140 and 142 compensate for any irregularities in the internal wallof device 10 to provide an effective seal. The piston material, in onepreferred embodiment, can be formed of any of four grades of Santoprene®271 material, the most preferred grade being 271-55.

In one embodiment, the piston 29 includes a cylindrical body portion 145positioned within the first wall section 12a. The piston 29 includes thecylindrical first or central body member 145 with first and secondpiston ends 144 and 146 respectively. The deformable seals 140 or 142are formed at first and second piston ends 144 and 146 respectively. Inone particular embodiment, the deformable seals 140 and 142 include aflared, conical skirt member or section 148. As best shown in FIGS. 21and 22, the skirt 148 extends radially outward from the central bodymember 145 to terminate at a position spaced apart therefrom. Referringagain to FIG. 21, a metal location detection member 150 is formed withinthe central cylindrical body member 145. The skirt member 148, extendsradially outward at an oblique angle plane generally defined by thesurface of the central body member 145. As a result, the distal end ofthe piston 29 are biased radially outward when articulating within theinner diameter of the first wall section 12a. The thickness of the skirtenables the skirt to provide sufficient wiping pressure to the insidesurface of the first wall section without invoking such pressure as tocause the skirt to fold over.

Referring again to FIG. 20, first wall section 12a at its end distantfrom lead end 9 defines and forms an open end having a circumference forforming a lap joint 152 with wall section 12b. Second wall section 12bdefines rear end 8 and it surrounds that portion of internal compartment18 which initially contains an expandable driving means, hereillustrated by expandable driving members 25a-f. Second wall section 12bat its end distant from rear end 8 defines and forms an open end havinga circumference for forming lap joint 152. Second wall section 12b isadapted with buttress 56 for strength and precision of manufacture.Preferably the buttress is shaped to provide a smooth surface transitionbetween wall sections 12a and 12b to minimize irritation leading toencapsulation.

Lap joint 152 includes, in the illustrated embodiment, lap joints 152aand 152b, reciprocally received one within the other for matingengagement when the two edges are assembled together. The lap joints152a and 152b are of such a design as to provide a strong mechanicallyand hydrostatically intact seal when they are bonded together with anadhesive, such as a pressure-sensitive contact adhesive, amoisture-curing adhesive, an ultraviolet-curing adhesive or the like.While FIG. 16 shows the two wall sections assembled with the lap joint152a of first wall section 12a enclosing the outside of the lap joint152b of second wall section 12b, this arrangement is not critical andmay be reversed. However, the illustrated embodiment is preferred sinceit provides additional restraint on the second wall section or membranecup 12b pulling away from the lap joint. In addition, if the materialused in the formation of the wall section surrounding the osmoticdriving member, for example wall section 12b, is not as strong as thematerial used in the formation of the portion surrounding the beneficialagent 7, for example first wall section 12a, then the weaker material ispreferably positioned or disposed to the inside or inserted within thestronger material. For example, if cellulose acetate butyrate is usedfor the portion surrounding the osmotic driving member and polypropyleneis used to surround the beneficial agent 7, then the cellulose acetatebutyrate wall is preferably on the inside of the polypropylene wall.

In a presently preferred embodiment, the exit passageway 13 and depot122 are occluded with a material such as wax that gets discharged,leaches or erodes when placed in the organic environment of use. Theimplant can be implanted into the peritoneal cavity using an implanter.

Generally, an implanter comprises a tubular member with a centrallongitudinal axial bore, a pointed, elongated, annular concavely beveledimplanting end and an implant-charging end. The implanting end and thecharging end communicate through a bore. A plunger adapted to beremovably inserted in the bore is designed for slidable movement thereinfor applying the necessary force for implanting the implant.Alternatively, the implant can be surgically or subcutaneously implantedin the peritoneal cavity.

Referring again to FIG. 16, first wall section 12a comprises acomposition that is substantially impermeable to the exchange of fluid,beneficial agent 7 and other ingredients contained in delivery system10. Wall section 12a, in a presently preferred manufacture, issubstantially impermeable to the ingress/loss of an external/internalfluid to serve as a means for substantially protecting a beneficialagent 7 that is sensitive to exterior fluid present in the environmentof use. Wall section 12a substantially restricts and prevents fluid frompassing through wall 12a and entering into compartment 18 in the regioncontaining a beneficial agent formulation. In one particular embodiment,when used in conjunction with bovine growth factors, including bovinesomatotropin, wall section 12a may be formed of a material whichprovides a reduced adherence of the beneficial agent 7 to the wall 12a.For example, the use of polypropylene in the construction of wall 12awill reduce the adherence of bovine somatotropin to the surface of wall12a.

In the preferred embodiment, wall section 12a is formed of polypropylenebecause of its excellent low permeability to water and because of itslow surface tension which facilitates non-adhesion of beneficial agent 7to the internal surface as compared with other materials such aspolycarbonates, which empirically appeared to result in increasedbearding on the respective wall surface/beneficial agent interface,especially when the beneficial agent included bovine somatotropin.Preparing polypropylene for bonding preferably includes preparing thesurface thereof to increase the likelihood of an effective seal. Thoseskilled in the art will recognize that this may be performed by variousmethods, a non-inclusive list includes, for example, by priming with achemical primer, abrading or knurling the surface, treatment with plasmaand the like.

Second wall section 12b is permeable to the passage of fluid in at leasta portion and it is substantially impermeable to the passage of otheringredients contained in delivery system 10.

Wall sections 12a and 12b optionally comprise a plasticizer that impartsflexibility and workability to the wall. Wall 12, comprising sections12a and 12b, is nontoxic and, in a preferred embodiment, it maintainsits physical and chemical integrity; that is, wall 12 does not erodeduring the dispensing period.

Compartment 18 comprises a beneficial agent 7 formulation, whichbeneficial agent 7 formulation comprises a beneficial agent 7,identified by dots, and a pharmaceutically acceptable carrier 21,identified by wavy lines. The pharmaceutically acceptable carrier mayinclude more than one ingredient, such as a buffer 22, identified byhorizontal dashes; a pharmaceutically acceptable vehicle 23, identifiedby vertical lines; a pharmaceutically acceptable surfactant 24,identified by slanted lines; and other formulation ingredients, as areknown in the art.

Compartment 18 further comprises an expandable means or expandabledriving member 25 optionally comprising members 25a-f. Expandabledriving member 25 optionally comprises an osmagent homogeneously orheterogeneously blended with binder to form expandable driving member25.

Compartment 18 may optionally comprise a partition layer 27. Partitionlayer 27 may optionally include, as in this embodiment, a piston 29,discussed in more detail with respect to FIG. 20. The partition layer 27may include a portion which may be positioned between the drive piston29 and the expandable driving member 25. The partition layer maycomprise a composition that is substantially impermeable to the passageof fluid, and it further may act as a seal and restrict the passage offluid present in the expandable driving member into the beneficial agent7 formulation. Piston 29, alone or in cooperation with other portions ofthe partition layer 27, operate to essentially maintain the integrity ofthe beneficial agent 7 layer and the driving member layer 25. Portionsof the partition layer 27 acts also to insure that the expanding drivingforce generated by the expandable driving member 25 is applied directlyagainst piston 29 and thus is exerted on the formulation in compartment18.

In operation, as the expandable driving means 25 absorbs and imbibesfluid through fluid-permeable second wall section 12b from theenvironment of use, it expands and pushes against piston 29 causingpiston 29 to slide inside compartment 18. The piston may be lubricated,for example, using a silicone lubricant having the same characteristicsas DOW 360 medical fluid 1000 cs. Piston 29 moves towards exitpassageway 13, driving the beneficial agent 7 formulation in chamber 18through passageway 13 for delivering the beneficial agent 7 to theenvironment of use. Second wall section 12b is telescopically capped bythe engaging first wall section 12a. The two sections can be joinedtogether by adhesive bond or various techniques such as solvent weld,thermal weld, ultrasonic weld, spin weld, induction weld, mechanicallock or by similar welding or bonding operations which may also be usedin appropriate cases.

Delivery device 10 in FIG. 20 further comprises lead end 9, rear end 8,internal compartment 18, beneficial agent 7, pharmaceutically acceptablecarrier 21, pharmaceutically acceptable buffer 22, pharmaceuticallyacceptable vehicle 23, and a pharmaceutically acceptable surfactant 24.In addition, a salt such as NaCl or KCl may be present in amounts of1-4% by weight to assist stabilizing the state of formulation.

In a presently preferred embodiment, delivery device 10 comprises aplurality of expandable means members 25a-f initially housed in secondwall section 12b. This configuration is merely illustrative and theremay be any number of driving means present. Generally, there are fromone to six expandable driving members; however, this number is notcontrolling. The expandable driving members in a presently preferredembodiment are formed as depots or layers and comprise like or unlikecompositions. For example, driving members 25a-f can be made as tabletscomprising like osmopolymers or like osmagents, or they can compriseunlike osmopolymers or unlike osmagents, or one or more of the memberscan be a composition comprising an osmopolymer together with anosmagent. The members can be the same or they can be different.

Referring again to FIG. 16, end cap 38 further comprises a depot 122 influid communication between internal chamber 18 and exit s passageway13. Depot 122 can receive a material which is discharged, leached oreroded away during use. Preferably the material is wax or anothermaterial which can be discharged and depot 122 is sized to provide forsufficient present to discharge the material through passageway 13. Thismaterial serves several purposes: it seals delivery device 10 to preventpremature delivery of a beneficial agent 7 from delivery device 10 andto prevent evaporation of carrier components such as water duringstorage, it helps maintain the clean or optionally sterile environmentinside delivery device 10, and it protects the ingredients inside thedelivery device from oxidation by air and also protects the beneficialagent 7 from dilution by body fluids following implantation. Moreparticularly, the seal 30 consistently releases at the same pressureusing a 145 A wax in an end cap construction as described elsewhere inthis application. In one preferred embodiment, the seal 30 releases at apressure greater than 5-10 psi, more preferably greater than about 9psi.

First wall section 12a, which surrounds the internal space ofcompartment 18 initially occupied by the beneficial agent 7 formulation,comprises a composition that does not adversely affect the beneficialagent 7, the osmopolymer, the osmagent, other ingredients in device 1 0,the host, or the like. First wall section 12a comprises a compositioncomprising means that substantially limits or prevents the passage of anexternal fluid into device 10. The phrase, "substantially limits orprevents," as used herein, indicates the volume of external fluidpassing through first wall section 12a is substantially negligible, thatis, about zero up to about 1 mL per day (see example 2 discussed morefully elsewhere in this application). Typical compositions for formingfirst section 12a are discussed in U.S. Pat. Nos. 5,057,318 for example.

The second wall section 12b comprises a composition comprising meansthat aid in controlling fluid flux into the compartment area occupied bythe expandable driving member 25. The composition is semipermeable; thatis, it is permeable to the passage of external fluids such as water andbiological fluids and it is substantially impermeable to the passage ofbeneficial agents, osmopolymers, osmagents, and the like. Typicalcompositions comprising semipermeable materials for forming wall 12b areknown in the art, a non inclusive list includes the group consisting ofa cellulose ester, a cellulose ether and a cellulose ester-ether,including, for example, cellulose acetate butyrate. These cellulosicpolymers have a degree of substitution, D.S., on the anhydroglucose unitfrom greater than 0 up to 3, inclusive. By "degree of substitution" or"D.S." is meant the average number of hydroxyl groups originally presenton the anhydroglucose unit comprising the cellulose polymer that arereplaced by a substituting group. Representative fluid-permeablematerials are discussed in U.S. Pat. Nos. 4,874,388, 5,034,229, and5,057,318, for example. The amount of semipermeable materials presentlypreferred in wall 12b is from about 20% to 100%. In the presentlypreferred form, the wall is formed of polypropylene equivalent tomedical grade polypropylene PD626 sold by Himont, because of itsexcellent low water transport qualities and the relative low surfacetension relative to the beneficial agent 7 formulation as compared toother polycarbonates, especially when the beneficial agent is bovinesomatotropin.

Representative materials that can be used to regulate further the fluidflux of wall 12b include materials that decrease the fluid flux andmaterials that increase the fluid flux of wall 12b. Representativematerials optionally added to wall 12b for either decreasing orincreasing the flux are presented in U.S. Pat. Nos. 5,034,229 and5,135,523.

First wall section 12a and second wall section 12b optionally comprise anontoxic plasticizer. Representative plasticizers suitable for formingwall 12a or wall 12b are well known in the art and examples arepresented in U.S. Pat. Nos. 5,034,229 and 5,135,123.

Delivery device 10 in its compartment 18 can also comprisepharmaceutical carrier 21. Carrier 21 may optionally include viscositymodulating vehicles (23), buffers (22), surfactants (24), dyes, andother additives known in the art, examples of which are disclosed inU.S. Pat. Nos. 5,034,229 and 5,135,123 to comprise the beneficial agent7 formulation.

In a presently preferred embodiment, the beneficial agent 7 is bovinesomatotropin, in an amount of from about 25% to about 60% by weight (wt%) of the beneficial agent 7 formulation, preferably from about 30 wt %to about 45 wt %.

The expandable driving means 25 initially surrounded by second wallsection 12b and operable for pushing the beneficial agent 7 composition20 from delivery device 10 comprises, in a presently preferredembodiment, an osmopolymer. The osmopolymers interact with water andaqueous biological fluids and swell or expand to an equilibrium state.The osmopolymers exhibit the ability to swell in water and to retain asignificant portion of the imbibed and absorbed water within the polymerstructure. The expandable driving means 25 in another preferredembodiment comprises an osmagent. The osmagents are known also asosmotically effective solutes and they are also known as osmoticallyeffective compounds. The osmotically effective compounds that can beused include inorganic and organic compounds that exhibit an osmoticpressure gradient across a semipermeable, i.e. a fluid permeable, wall.The expandable driving member 25 yet in another preferred embodimentcomprises an optional osmagent dispersed within the osmopolymer. Theosmagent or osmopolymer can comprise a tablet or a layer or can bepressed into second wall section 12b. The osmagent or osmopolymer can bein any suitable form such as particles, crystals, pellets, granules, andthe like, when pressed into a tablet layer and into wall section 12b.Osmagents and osmopolymers are known to the art in U.S. Pat. Nos.3,865,108, 4,002,173, 4,207,893, 4,327,725, 4,612,008, 5,034,229, and5,135,123 for example.

Piston 29, positioned between the beneficial agent composition and theexpandable driving member 25, is a means for maintaining the separateidentity of the beneficial agent composition and the driving member, fortransmitting the force generated by the driving member against thebeneficial agent composition, and for substantially restricting thepassage of fluid between the beneficial agent composition and thedriving member.

End cap 35, illustrated in FIG. 16, by being impermeable to fluid,having a passageway whose diameter length of a sufficient diameter andlength; and a sealant preventing passage therethrough up to apredetermined threshold pressure, providing protection for thefluid-sensitive beneficial agent. The end cap provides a means forsimply and conveniently assembling the device and particularly forfilling the device with internal components such as the driving members,the partition and the beneficial agent formulation. Materials forforming end cap 38 may be chosen from those materials useful inpreparing impermeable first wall section 12a.

The terms "exit means" and "exit passageway", as used herein, comprisemeans and methods suitable for the metered release of the beneficialagent 7 from compartment 18 of delivery device 10. This includesmaintaining sufficient efflux or outward velocity of the beneficialagent to prevent an inward flow of fluid from the external environmentto dilute the beneficial agent formulation in the portion of thecompartment comprised by the first wall section. The exit passageway 13includes at least one passageway, orifice, or the like, through firstwall section 12a for communicating with compartment 18. The expression"at least one passageway" includes aperture, orifice, bore, pore, porouselement through which the agent can migrate, hollow fiber, capillarytube, porous overlay, porous insert, and the like. The expression alsoincludes material that gets discharged, erodes or is leached from thewall in the fluid environment of use to produce at least one passagewayin delivery device 10. The expression includes structuralcharacteristics that concentrate stress at a precise point in the wallso that only a small amount of force will induce breakage in the wall,yielding a passageway through the wall from compartment 18 to theoutside of the device. A passageway or passageways can be formed by thedischarge, as a result of the pressure created by the expandable memberfor example, of a material such as a wax. The passageway can have anyshape such as round, triangular, square, elliptical, and the like, forassisting in the metered release of beneficial agent from deliverydevice 10. Delivery device 10 can be constructed with one or morepassageways in spaced-apart relations or more than a single surface of adosage form. Passageways and materials, equipment and methods forforming passageways are disclosed in U.S. Pat. No. 5,034,229.

Delivery device 10 can be manufactured by standard manufacturingtechniques. In one process, the first wall section 12a and the secondwall section 12b are independently injection molded or extruded into thedesired shape. Then, the first wall section 12a is filled with thebeneficial agent composition. The second wall section 12b is filled withan expandable driving member or members, and the piston 29 is next addedthereto in layered arrangement. Optionally, the piston 29 may be addedto the first wall section 12a after filling the wall section withbeneficial agent, in addition to, or instead of, the partition layeradded to second wall section 12b, Next, the two sections at their openends are slid together.

The delivery device can be manufactured for delivering numerousbeneficial agents, including drugs, at a controlled rate to a presentlypreferred biological environment of use such as warm-blooded animals,including humans; ruminants, such as bovines and sheep; porcines, suchas hogs and swine; horses; and the like. The delivery devices providefor high loading of a beneficial agent and for its improved delivery inbeneficially effective amounts (that is, amounts that provide abeneficial effect) over time. It is to be understood that the deliverydevices can take a wide variety of shapes, sizes and forms adapted fordelivering beneficial agents to environments of use. For example, thedevices manufactured as delivery devices can be used for dispensing abeneficial agent in the anal-rectal passageway, in the cervical canal,as an artificial gland, in the vagina, as a subcutaneous orintraperitoneal implant, and the like. The delivery devices can be usedin hospitals, nursing homes, outpatient clinics, sickrooms, veterinaryclinics, farms, zoos, and other environments of use.

EXAMPLE A1

A delivery device manufactured in the shape of an implantable deliverydevice is manufactured as follows.

An expandable driving member was prepared by first adding 10 liters ofwater and 526 g of polyvinylpyrrolidone to a stainless steel containerand mixing the components for 1 hr to obtain a smooth binder solution.Next, approximately 20 kg of sodium chloride was milled in a mill to anumber 21 size mesh screen. Then, 17.5 kg of the milled sodium chlorideand 7.5 kg of sodium Carbomer®, a sodium salt of a polyacrylic polymer,were transferred to the granulator bowl of a fluid bed granulator and2.46 kg of binder solution was slowly sprayed onto the materials in thegranulator. Granules were formed in this manner. Next, the granulatedmaterial was sized by forcing it through a 0.0469 in mesh screen in ascreen separator. Then, the granulation was divided into two 2.8 kgsub-batches. For each sub-batch, 130 g of magnesium stearate was addedand the ingredients were blended for 3 min at 9 rpm to produce ahomogeneous expandable driving composition. The composition next waspressed into osmotically active tablets in a tablet press at a pressureof 2,000 lbs to produce a round, flat-faced 266 mg tablet as anexpandable driving member.

The semipermeable wall (membrane cup) that surrounds a compartment forcontaining the osmotically active tablets was prepared as follows.First, 1.0 kg of tributyl citrate and 9.0 kg of cellulose acetatebutyrate were dry mixed in a mixer for 30 min. This produced apolymer/plasticizer blend of 90/10 ratio for the rate-controllingsemi-permeable second wall section 12b. The blend was then injectionmolded into a semi-permeable membrane cup of the desired shape with anopen end for receiving an expandable driving member and for mating withthe forward wall section, whose preparation is as follows.

The impermeable first wall section 12a of the delivery device 10 whichforms the compartment holding the beneficial agent 7, is prepared byblending the polypropylene (Himont PD626) with a blue colorant (0.1 FD &C blue lake). The mixture is then injection molded into the first orforward impermeable wall section 12a in the desired shape, with the opensecond end 34 for mating with the semi-permeable second wall section ormembrane cup 12b and an open forward or lead end 32 for the end cap 38That portion of the first wall section 12a which mates with thesemi-permeable second wall section or membrane cup 12b is molded with adiamond shaped pattern over a portion of its surface to enhance theadhesive bond between it and the membrane cup. Surface preparationensures satisfactory adhesive bonding of polypropylene to othermaterials. In the case of the first wall section 12a, in addition to themechanical configuration described above, this may be accomplished byeither applying a primer to the glue-joint area or by treating thesurface with a plasma made from a mixture of oxygen andtetrafluromethane gases prior to applying the adhesive. That matingportion of the first or forward wall section which mates with the endcap 38 is molded with circumferential, rectangular-shaped mortise 102 tofacilitate ultrasonically welding the end cap 38 to the forward wallsection 12a as described more fully elsewhere in this application.

The end cap 38 was prepared by blending polypropylene (Himont PD626)with a blue or white colorant (0.1% FD & C blue lake or 1.0% titaniumdioxide, respectively). This mixture is then injection molded to formthe end cap 38, as described more fully earlier in this application,having the exit aperture with a 0.017 inch diameter approximately 0.1inches long, an internal cavity for containing a wax sealant material,and a precisely determined circumferential configuration around theouter perimeter of the end cap 38 to facilitate ultrasonic welding ofthe cap to the forward wall section 12a. This configuration includes awedge shaped energy director with an included angle of 56°, which isbeneficial to achieving a high quality ultrasonic weld with crystalline,polymeric materials being joined. The internal cavity is filled withmolten wax (Witco 145), which solidifies to form a seal to the orificeport.

The piston 29 is prepared by insert injection molding Monsanto brandthermoplastic elastomer sold under the brand name "Santoprene® 271-55",into the piston with a circumferential, cantilevered lip at each end anda metal detection core in its center. The metal core is cylindrical inshape with a flat face at each end and is manufactured in a separateprocess by sintering at 1300° F. a metal alloy consisting of nickel andiron in a 50/50 ratio. The metal core is inserted into the mold when itis in the open position, and the thermoplastic elastomer is injectedaround it during the injection molding process. The piston 29 thusformed is lubricated with silicone medical fluid to facilitate movementof the piston inside the device during assembly and operation and tominimize piston set during storage.

The delivery device 10 is partially assembled by first charging thesecond wall section or semi-permeable membrane cup 12b with six of theosmotic tablets 25a-f. The second wall section 12b is then partiallyinserted into the impermeable first or forward wall section 12a of thedevice 10 and two drops of moisture-cured cyanoacrylate adhesive aredropped onto the exposed portion of the joint between the first andsecond wall sections, where the adhesive is drawn into the remainder ofthe joint by capillary action. The first and second wall sections 12 and12b are then fully inserted to form a mechanically strong, water-tightseal. The lubricated piston 29 is then inserted through the remainingopen end 32 of the first or forward wall section 12a, using a tool whichallows air to pass by the piston 29 as it is moved into position againstthe osmotic tablets 25a-f and insert the piston within the wall sectionwithout having the skirt member rolled. The tool used is a thin-walledfunnel open at both ends having an internal chamber for receipt of thepiston therein.

Next, the delivery device subassembly, comprised of the second wallsection or membrane cup 12b, the osmotic tablets 25a-f, the impermeablefirst or forward wall section 12a and the piston 29, is filled with 2250mg of the beneficial agent 7 formulation at 35° C. The formulation iscomprised of 36.5%±1.5% for Zn-bST in a phosphate buffer, glycerols,wetting agent, salt excipient blend where the w/w/w/w proportions ofphosphate buffer, glycerol, Tween-80, and KCl are 48.38/48.38/0.24/3.0respectively. The phosphate buffer is 60:40 monobasic:dibasic sodiumphosphate, and the molarity is 0.45. Then, a waxed end cap 38 is placeinto position on the open lead end 9 of the first wall section 12a byultrasonic welding. The filled implant 10 is heat treated after beingplaced into a sterile package, for example, by heating the about 40° C.for about 16 hours.

EXAMPLE A2

The pistons of the configuration described in Example A1 were tested asfollows:

A formulation of ZnbST in a phosphate/glycerol/Tween/NaCl excipient wasprepared using titrated water (³ H₂ O)). The specific activity of thelabelled water was 1.0 mCi/ml, and should be sufficient to provide adetection limit of 1 mgm of water. The formulation was loaded into 10 mmosmotic implants with two different piston designs (1.0× and 1.5×), anda third group that had the compartment surrounding the osmotic drivingmember prehydrated.

                  TABLE 1                                                         ______________________________________                                        Pump configurations                                                           Group         Piston  Pre-hydration                                           ______________________________________                                        1             1.0x    no                                                      2             1.5x    no                                                      3             1.0x    yes                                                     ______________________________________                                    

The implants were sampled in duplicate for group 1, and triplicate forgroups 2 and 3, at intervals of 0, 3, 6, 12 and 18 weeks. Formeasurement of total water transport to the osmotic driving members,e.g. salt tablets, of the internal chamber 18 surrounded by thesemi-permeable wall section 12b, the second wall section 12b wasseparated from the first wall section 12a and the end cut off. Salttablets were expelled and dissolved in water. An aliquot of the solutionwas added to the liquid scintilallation cocktail and counted by standardliquid scintillation counting techniques. Table 2 lists the individualmeasurements of the total water content.

                  TABLE 2                                                         ______________________________________                                        TRANSPORT OF WATER FROM THE FORMULATION                                       COMPARTMENT TO THE ENGINE COMPARTMENT DURING                                  STORAGE AT 4 C.                                                               Group/                                                                        Replicate                                                                            Week 0   Week 3   Week 6 Week 12                                                                              Week 18                                ______________________________________                                        1/1    12       37       75     7413*  130                                    1/2    12       50       68     98     148                                    1/3    --       --       --     --     162                                    2/1    460      43       66     331*   515*                                   2/2    14       41       67     97     150                                    2/3    1209*    45       235*   102    146                                    3/1    4        56       82     114    189                                    3/2    101*     46       65     711*   230*                                   3/3    5        51       76     112    139                                    ______________________________________                                         *Possible statistical outlier (greater than 3 standard deviations from        mean excluding theses points).                                           

FIG. 23 is a graph depicting the relationship between mgms of H₂ Oby-passing the piston versus time (weeks).

FIG. 24 is a graph showing mgms of H₂ O by-passing the piston versustime excluding outliers.

A variable amount of water (0.1-7 mg) transferred from the portion ofthe internal compartment 18 surrounded by the first wall section 12a tothe portion surrounded by the second wall section 12b during the fillingprocedure for approximately 25% of the implants 10. There was a highpump to pump variability at all time points, on top of a small increasedue to subsequent water transport from the internal compartmentsurrounded by the first wall section 12a to the salt tablets. The linearregression estimates of the rate of water transport along with 95%confidence intervals were as follows:

All data included: 20.0±8.9 mgms/week

excluding outliers: 7.1±0.1 mg/week

Thus, the worst case estimate (upper 95% confidence interval with alldata included) was 28.9 mgms per week, or approximately 1.5 milligramsper year. The best case estimate (lower confidence interval excludingoutliers) was 7.0 mgms per week, or 0.36 milligrams per year. Thereforeit was concluded, assuming the acceptable limit set by the amount ofwater that can be lost from the formulation without exceeding a 1%increase in protein assay, is approximately 60 milligrams, that thepiston tested in these experiments was deemed adequate to maintainseparation between the portion the internal compartment 18 surrounded bythe first wall section 12a and the portion of the internal compartment18 surrounded by the semipermeable second wall section 12b for theanticipated shelf life of five years or more.

EXAMPLE A3

Delivery devices of the configuration as described in Example A1 weretested in vivo as follows.

Example A3a (11466) Weekly Subcutaneously Administered Pellets

A study was undertaken to determine the effect of 40 or 80 mg A-bSTpellets administered subcutaneously weekly during a 84-day beef cattlestudy on 1) growth, 2) feed efficiency and 3) carcass composition.

One hundred eighty Angus X Hereford beef steers weighing approximately350 kg (770 lbs) were used. Stocking density was 5 animals per pen. Thetrial consisted of 180 steers with replicates of 12 pens (60 animals)per treatment group (control, 40 mg bST/wk, and 80 mg bST/wk). The studylasted 84 days (12 weeks) exclusive of the pretreatment period. The dietfor all animals, on a dry matter basis, contained 16% crude protein("P"). Potable water was available ad libitum. Pens were randomlydistributed among treatments:

                  TABLE 3                                                         ______________________________________                                        Treatment                                                                     Trial  Group     Pens   Animals  Description                                  ______________________________________                                        1      1         12     60       Control                                      1      2         12     60       40 mg/wk A-bST                                                                Pellets                                      1      3         12     60       80 mg/wk A-bST                                                                Pellets                                      ______________________________________                                    

The animals were slaughtered for carcass analysis. The results are shownon the following Table:

                  TABLE 4                                                         ______________________________________                                        TREATMENT                                                                                            40 mg/wk   80 mg/wk                                    Parameters   Control   bST Pellets                                                                              bST Pellets                                 ______________________________________                                        Initial Body Wt (kg)                                                                       390.3     390.3      390.3                                       Final Body Wt (kg)                                                                         499.5a    495.0a     510.4b                                      Carcass Wt. (kg)                                                                           308.3     304.3      312.2                                       Dressing Percent                                                                           61.7       61.5       61.2                                       Carcass Gain Response                                                                      --        No Gain     39%                                        Non-Carcass  --        No Gain     61%                                        Gain Response                                                                 ______________________________________                                         a, b  different superscripts indicate that numbers in a row are               significantly different (p <.05)                                         

It was observed that neither dressing percentage nor carcass weight weresignificantly increased. Further, at a higher dosage, most of theincrease in body weight due to bST treatment was allocated to thenon-carcass components.

Example A3b Weekly Subcutaneous or Intraperitoneal Pellets

A study was undertaken to determine whether the effect of 80 mg A-bSTpellets during an 84-day beef cattle study was comparable whenadministered subcutaneously and intraperitoneally.

Two hundred seventy Angus X Hereford beef steers weighing approximately350 kg (770 lbs) were bought and divided into three study groups.Stocking density was 5 animals per pen. Each study group consisted ofreplicates of 6 pens (30 animals) per treatment group (control, 40mgbST/wk subcutaneous pellet, and 80 mgbST/wk intraperitoneal pellet).The study lasted 84 days exclusive of the pretreatment period. The dietfor all animals, on a dry matter basis, contained 16% crude protein.Potable water was available ad libitum. Pens were randomly distributedamong the treatments:

                  TABLE 5                                                         ______________________________________                                        Trial                                                                              Treatment  Pens   Animals Description                                    ______________________________________                                        2    1          12     60      Control                                        2    2          12     60      80 mg/wk A-bST                                                                Subcutaneous (SQ)                                                             Pellet                                         2    3          12     60      80 mg/wk A-bST                                                                Intraperitoneal (IP) Pellet                    3    1          12     60      Control                                        3    2          12     60      80 mg/wk bST SQ                                                               Pellet                                         3    3          12     60      80 mg/wk bST IP                                                               Pellet                                         4    1          12     60      Control                                        4    2          12     60      80 mg/wk A-bST SQ                                                             Pellet                                         4    3          12     60      80 mg/wk A-bST IP                                                             Pellet                                         ______________________________________                                    

The animals were slaughtered for carcass analysis. The results are shownin the following Tables:

                  TABLE 6                                                         ______________________________________                                        TREATMENT                                                                                            80 mg/wk SQ 80 mg/wk IP                                Parameters   Control   bST Pellets bST Pellets                                ______________________________________                                        Carcass Wt. (kg)                                                                           395.1     395.0       397.7                                      Final Body Wt (kg)                                                                         493.7a    499.5a      507.8a                                     Carcass Wt. (kg)                                                                           304.2     304.2a      311.2a                                     Dressing Percent (%)                                                                        61.6a     60.8b       61.2ab                                    Carcass Gain (%)                                                                           --         0%          61%                                       Response                                                                      Non-Carcass (%)                                                                            --        100%         39%                                       Gain Response                                                                 ______________________________________                                         a, b  different letters indicate that numbers in a row significantly          different (p <.05)                                                       

It can be seen that, while the dressing percentage ofsubcutaneously-treated cattle was significantly decreased relative tothe control, the dressing percentage of intraperitoneally-treated wasnot significantly changed relative to the control.

Example A3b Combination of Intraperitoneal bST Osmotic Pump and EstrogenPellets

A study was undertaken to determine whether the effects ofintraperitoneal release of bST, of estrogen pellets, or of the combinedeffects of the two.

Two hundred fifty-six cross-bred large frame steers weighingapproximately 430 kg (948 lb) were assigned to a control group and threetreatment groups and implanted with intraperitoneal bST pumps or/andestrogen pellets. The bST formulation used was a 35% An bST load in aphosphate buffer, glycerol, Tween-80 and KCl excipient. The w/w/w %proportions respectively were 48.38/48.38/0.24/0%. The phosphate bufferwas 60:40 monobasic:dibasic sodium phosphate at 1.0M. The time ofrelease of both bST and estrogen was 87 days prior to slaughter. Theresults are shown in the following Table.

                  TABLE 7                                                         ______________________________________                                        TREATMENT                                                                                       12 mg/d   0 bST/  12 mg/d                                                     bST 0     200 ug/d                                                                              bST//200 ug/d                             Parameters                                                                             Control  Estrogen  Estrogen                                                                              Estrogen                                  ______________________________________                                        Initial  430.3    430.3     430.3   430.3                                     Body Wt                                                                       (kg)                                                                          Final Body                                                                             544.9a   552.2b    567.1c  576.4d                                    Wt (kg)                                                                       Carcass Wt                                                                             334.2a   340.3b    349.3c  359.7d                                    (kg)                                                                          ______________________________________                                        Parameters                                                                             Control  Estrogen  Estrogen                                                                              Estrogen                                  ______________________________________                                        Dressing  61.3a    61.6a     61.6a   62.4b                                    Percent                                                                       (%)                                                                           Carcass  N/A       84%       68%    112%                                      Gain                                                                          Response                                                                      Non      N/A       16%       32%    -12%                                      Carcass                                                                       Gain                                                                          Response                                                                      ______________________________________                                         a,b different superscripts indicate that number in a row are significantl     different (P <.05)  what about c and d                                   

These results indicated that a significant improvement in dressingpercentage and carcass weight were achieved by intraperitoneal osmoticpump release of bST concurrent with estrogen treatment.

Example A3c Combination of Intraperitoneal bST Osmotic Pump and EstrogenPellet

A study was undertaken to determine performance of intraperitonealosmotic pumps in finishing cattle concurrently being administeredestrogen. Six hundred seventy-two cross-bred large frame cattle weighingapproximately 412 kg were bought and assigned to a control group and sixtreatment groups of 96 cattle each. The cattle were implanted withintraperitoneal osmotic pumps capable of delivering 6, 12, 15 or 18 mgbST per day during an 84-day period ending with slaughter. The cattlereceived estrogen pellets during a 126-day period ending with slaughter.The estrogen release is estimated at about 200 μg/d. The results areshown in the following table.

                                      TABLE 8                                     __________________________________________________________________________    TREATMENT                                                                     load      30%      40%      45%                                               Parameters                                                                          Control                                                                           6 μg/d                                                                         12 μg/d                                                                         6 μg/d                                                                         12 μg/d                                                                         12 μg/d                                                                        18μg/d                                     __________________________________________________________________________    Initial                                                                             411.9                                                                             411.9                                                                             411.9                                                                              411.9                                                                             411.9                                                                              411.9                                                                             411.9                                         Body Wt                                                                       (kg)                                                                          Final Body                                                                          555.1a                                                                            565.6bc                                                                           568.7bc                                                                            569.6c                                                                            561.8b                                                                             563.5bc                                                                           566.5bc                                       Wt (kg)                                                                       Carcass Wt                                                                          343.0a                                                                            353.1bc                                                                           357.2d                                                                             355.4cd                                                                           350.8b                                                                             351.3b                                                                             53.8bcd                                      (kg)                                                                          Dressing                                                                             61.8a                                                                             62.4b                                                                             62.8b                                                                              62.4b                                                                             62.4b                                                                              62.4b                                                                             62.5b                                        Percent                                                                       Carcass                                                                             --   96%                                                                              104%  86%                                                                              116%  99%                                                                               95%                                          Response                                                                      Non-  --   4% -9%   14%                                                                              -16%  1%  5%                                           Carcass                                                                       Response                                                                      __________________________________________________________________________

The results confirm that concurrent intraperitoneal treatment offinishing beef cattle with bST and estradiol significantly increasedressing percentage and carcass weight and furthermore allocated most ofthe increased weight to the carcass components.

EXAMPLE A4

FIG. 25 is a graph depicting the real time pressure release for a sealof Multiwax X-145a wax having a thickness of 0.050 inches. The pressureat which the seals blew was between 6 and 9 psi from exit passageway ofhaving a 0.017 diameter and a length of 0.100 inches.

Thus, an exit passage having a 0.017 inch diameter and a length of 0.100inches, in fluid contact or abutted by a seal of 0.050 thick, wouldburst the seal between about 6-9 psi.

EXAMPLE A5

FIG. 26 is a graph showing the effect of the exit port aperture diameteron the diffusion of water using an exit passageway length of 0.100inches and specified diameter. Empirical observations of the respectivedevices indicate that the beneficial agent formulation turned white inall devices with 0.050 inch diameter outlets with small pockets of waterentrained in the formulation. The beneficial agent formulation was clearin all devices having an exit port aperture of about 0.017 inches indiameter.

Thus an exit aperture having a diameter of 0.017 inches providessufficient outward velocity or efflux of the beneficial agent from thecompartment defined by the first wall section, i.e., "substantiallylimits or prevents" diffusion of fluid back into the internalcompartment defined by the first wall section under these conditions ofuse obviously the diameters and lengths of the aperture needed to effectthe desired flow rate will vary with the optimum conditions ofdelivery/usage of the particular beneficial agent.

The devices use means for the obtainment of precise release rates in afluid environment of use while simultaneously maintaining the integrityof the device and the stability of the fluid-sensitive beneficial agent7 within the device.

SUPPLEMENTAL EXEMPLARY EMBODIMENT B Methods For Use of the Invention

The invention may be used in a method of preparing beef cattle in thefinishing stage of growth for slaughter. The finishing stage of growthis the final stage of growth before slaughter, and follows the stockerstage of growth when the bovine receives nutrients primarily frompasturage or hay, optionally with feed supplementation, which in turnfollows the calf or suckling stage when the calf receives nutrientsprimarily from its mother.

Cattle in the finishing stage of growth are generally nonlactatingbovines (steers or heifers) of 12 months (or even as low as 3 months) to2 years of age who are undergoing rapid growth. The finishing stage ofgrowth can be regarded as beginning when the typical beef stocker isabout 700 pounds (about 320 kg) of weight. Such animals will usually beslaughtered when a weight of about 1000 or 1300 pounds (about 450 kg or600 kg) or more is reached.

The finishing stage of growth is a period of time during growth when thebovine is of sufficient size and age when supplied with a suitable feedto undergo a rapid average daily weight gain, for example, an averagedaily gain of at least 1 kg/d, that is, when the rate of weight gain is1 or more than 1 kg/d. Typically, cattle during this phase of growth cangain in the range of about 1 to about 2 kilograms or even more per day.Preferably, the cattle are high-performance cattle capable of growth ata rate of greater than about 1.5 kg/d, most preferably at a rate greaterthan about 1.7 kg/d. The current limit of average daily gain (ADG)during finishing is about 3 kg/d; however, as higher performance cattleare developed, this limit may be exceeded. In any case, the range above1 or 1.5 etc. kg/d is finite and definite and will be known to thoseskilled in the art.

During the finishing stage of growth, the bovine feed may besupplemented with concentrated feed, richer than pasturage or hay indigestible proteins, carbohydrates, and fats. Typically, during thefinishing stages, feed grain may constitute from 12 to 80% or more ofthe animal's feed. The feed may contain from 12 to 16 percent or moreprotein or protein-equivalent nitrogen. National Research Council. (NRC)guidelines permit finishing at as low as 9% protein - equivalentnitrogen.

It has been found that feed efficiency, body and carcass weight anddressing percent are advantageously influenced when beef cattlereceiving an estrogenic agent are treated intraperitoneally with aneffective dose and rate of release of bST during this period of growth.

bST (bovine somatotropin) refers to any protein having bovinesomatotropin activity. The bovine somatotropin can be pituitary-derivedor recombinantly produced bovine somatotropin. The bST can be anaturally-occurring sequence or a sequence altered by addition ordeletion or substitution of one or more amino acids. All of these formsof bovine somatotropin are now well-known to those skilled in the art.

Examples of bovine somatotropin variants include, but are not limitedto, polypeptides having the following amino acid sequences withunspecified amino acid residues being the same as or similar to thenaturally occurring somatotropin:

    NH.sub.2 -met-phe(1)-pro(2) . . . leu(126) . . . phe(190)-COOH

    NH.sub.2 -met-phe(1)-pro(2) . . . val(126) . . . phe(190)-COOH

    NH.sub.2 -ala-phe(1)-pro(2) . . . val(126) . . . phe(190)-COOH

    NH.sub.2 -ala-phe(1)-pro(2) . . . leu(126) . . . phe(190)-COOH

    NH.sub.2 -phe(1)-pro(2) . . . leu(126) . . . phe(190)-COOH

    NH.sub.2 -phe(1)-pro(2) . . . val(126) . . . phe(190)-COOH

    NH.sub.2 -met-asp-glu-phe(1)-pro(2) . . . leu(126) . . . phe(190)-COOH

    NH.sub.2 -met-asp-glu-phe(1)-pro(2) . . . val(126) . . . phe(190)-COOH

    NH.sub.2 -met(4)-ser(5) . . . leu(126) . . . phe 190)-COOH

    NH.sub.2 -met(4)-ser(5) . . . val(126) . . . phe(190)-COOH

    NH.sub.2 -met-phe(10) . . . leu(126) . . . phe(190)-COOH

    NH.sub.2 -met-phe(10) . . . val(126) . . . phe(190)-COOH

The first variant in the list above, with a methionyl residue at theN-terminus, and a leucyl residue at position 126 may be specificallyreferred to as methionyl bovine somatotropin or "MBS", and the thirdvariant in the list above, with an alanyl residue at the N-terminus anda valyl residue at position 126 may be referred to as alanyl-valylbovine somatotropin or "ala-val BST" or "A-BST". Metal complexes of suchbST, such as zinc and copper complexes, may also be used and arereferred to as Zn-bST or Cu-bST. See, e.g., U.S. Pat. No. 4,863,736.

It is understood that the additional N-terminal methionyl residue on thevariants described above could also be removed, either during or afterexpression. It is also understood that one or more amino acids of thefollowing sequence -glu-arg-ala-tyr-ile-pro-glu- (which are numbers32-38 of the bovine somatotropin sequence set forth above) may bedeleted. This type of deletion is described in European PatentApplication, Publication Numbers 282,318, and 282,319, both of whichwere published Sep. 14, 1988. Other deletion variants with somatotropinactivity can also be used, such as deletion of amino acids 32-45.

The somatotropins found most effective for administration are thosewhich have an N-terminal group of methionine and are associated withzinc metal. See, e.g., U.S. Pat. No. B1 4,985,404, incorporated hereinby reference.

The formulation of bovine somatotropin for use in an osmotic implant maygenerally include a stabilizing polyol. The phrase "stabilizing polyol"means polyol, for example, with three hydroxyl groups, which maintainsthe somatotropin in a physically stable composition, i.e. thesomatotropin does not precipitate to an undesirable degree overreasonable storage or administration period. Glycerol is the preferredpolyol, however, other polyols may be used, such astris(hydroxymethyl)aminomethane.

The formulation may further include a physiologically compatible buffer,incorporated for maintaining the pH exhibited by the composition withina range in which the somatotropin is bioactive. Generally, the pHexhibited by the solution should be between a minimum of about 4.5 or,preferably about 5, or more preferably 5.7 and a maximum of the greaterof about 7 and about the isoelectric point of the somatotropin. Theisoelectric point for A-BST is 8.6. These isoelectric points are for thestandard monomeric forms obtained in bulk preparation of thesesomatotropins. Isoelectric points for other variants, other derivativesand other forms can be determined using standard techniques. For A-BST,the optimum pH is about between about 6.1 and about 7.5. Althoughvarious buffers can be used, it is preferred that the buffer be analkali metal phosphate. To provide buffering in the desired pH range, itis particularly preferable that the buffer be comprised substantially ofmonobasic:dibasic phosphates such as, for example, mono-or-di-sodium orpotassium phosphates at 1M or 0.45M or the like. Another effectivebuffer for controlling the pH in the desired range is a histidinehydrohalide such as histidine hydrochloride. Additional buffers thatmaintain this pH range are citrate buffers and acid addition salts oftris(hydroxymethyl)aminomethane, such as the hydrochloride salt. Thesetris(hydroxymethyl)aminomethane salts also contain hydroxyl groups andcan act as a stabilizing polyol in some circumstances. Any other bufferthat can maintain a pH in the desired range can be used.

It should incidentally be noted that direct measurement of the pH of thecomposition may not in all instances be practical. To provide apractical measurement, however, a small quantity such as a drop of thecomposition may be placed in about 10 ml of water, and the pH of theresulting mixture determined. It is believed that the actual pH of thecomposition is closely approximated by this measurement, but, in anyevent, it will be understood that the pH measured at such dilution isconsidered for purposes of this disclosure to be the pH exhibited by thecomposition itself.

In order to promote wetting of the somatotropin by the buffer/polyolexcipient during preparation of the formulation, a wetting agent, suchas a nonionic surfactant is preferably incorporated as well. Suchsurfactant also inhibits foaming. The surfactant can be present in theexcipient at amounts between about 0.005% and about 2.5% more preferablyabout 0.25%. A particularly preferred nonionic surfactant is apolyethoxylated sorbitan ester, such as a tri(polyoxyethylene) ester ofsorbitan mono-oleate, such as that sold under the trade designationTween 80 by ICI Americas Inc.

An advantage of the use of a buffered polyol excipient for thesomatotropin is the high loading achievable due to the high solubilityof the somatotropin in the excipient liquid. Despite the highconcentration of somatotropin in a composition which also contains asignificant fraction of water, the pH maintained by the buffer inhibitsthe formation of dimers and other aggregates. Although it has not beendetermined whether the somatotropin is true solution or colloidalsolution, it is desirable that the somatotropin does not precipitate orotherwise separate from the excipient, either on standing or under theinfluence of shear encountered in passage of the composition through thedischarge opening of an infusion pump. The concentration of somatotropinin the composition is at least about 10% by weight, preferably at leastabout 15% by weight, more preferably at least about 20% by weight andeven more preferably at least about 25% or even about 30% by weight. Thesomatotropin concentration may range as high as about 45% by weight. Thepolyol concentration may be at least about 20% by weight or 25% byweight and may range as high as 80% by weight or 70% by weight or 60% byweight or 50% by weight or 40% by weight. A relatively high glycerolcontent additionally provides a bacteriostatic effect. It is generallyconsidered that an excipient containing about 50% glycerol providesbacteriostatic effect. The osmotic implant may further contain anestrogenic agent, for example, 17-estradiol, at a concentration of about0.005 to about 1%, more preferably about 0.18 to about 0.72%.

Preferably, the formulation further comprises a wetting agent, such asnonionic surfactant with optimum concentrations between about 0.005% orabout 2.5% by weight. Except for the buffer salt, which in the case of aphosphate buffer may typically comprise 4% to 7% by weight, and thesodium or potassium chloride which may be added to stabilize theformulation, described below, the balance of the formulation typicallyis water. A preferred formulation contains at least about 7% water, morepreferably at least about 15% water, and even more preferably betweenabout 25% and about 35% by weight water.

Optionally an alkaline halide such as sodium chloride or potassiumchloride is added to the excipient prior to formulation withsomatotropin. It has been found that this facilitates maintaininghomogeneity of the formulation during filling of the implants, forexample, when using Zn-bST. Following addition of the somatotropin tothe excipient, the filled implant can be subjected to heat treatmentsfrom about 6 to 24 hours, preferably 16 hours, at a temperature betweenabout 35° C. and 50° C., preferably 39°-46° C., most preferably about40° C. Preferably the alkaline chloride comprises about 1 to about 4% byweight of the final formulation.

The formulation is normally a clear, homogeneous single phase. Theformulation appears as a solid or semisolid at typical storagetemperatures of about 4° C. The formulation decreases in viscosity toproduce a viscous liquid at the body temperature of an animal. In thisway, the formulation can be dispensable without being readily fluid atall temperatures.

As the concentration of somatotropin rises above 25%, the ratios ofwater and buffer to somatotropin preferably decline with increasingsomatotropin concentration so as to maintain a polyol concentration ashigh as practicable. However, polyol content is limited by viscosityconsiderations, and the maximum polyol concentration is about 40-45% forformulations having a hormone content about 25%. Higher polyolconcentrations provide a benefit in physical stability, but can resultin viscosity that makes handling difficult.

Preferably the bST is an aqueous suspension of bST formulated forrelease in an osmotic pump as hereinafter described. Such formulationscan include glycerol, monobasic and dibasic sodium phosphate buffer,Tween-80, an alkaline halide salt such as sodium chloride and/orpotassium chloride, but are not limited to these ingredients, inaddition to the active ingredients such as bST and the estrogenic agent.

The currently preferred formulation comprises 36.5% 1.5% for Zn-bST in aphosphate buffer, glycerols, wetting agent, salt excipient blend wherethe w/w/w/w proportions of phosphate buffer, glycerol, Tween-80, and KClare 48.38/48.38/0.24/3.0 respectively. The phosphate buffer is 60:40monobasic:dibasic sodium phosphate, and the molarity is 0.45.

The preferred composition containing an estrogenic agent comprises about0.06% to about 3.0% 17-beta-estradiol.

bST is intraperitoneally released in beef cattle in the finishing stagesof growth at an effective dose and rate for significantly increasing aparameter selected from the group consisting of body weight (BW),carcass weight (CW), average daily gain (ADG) or feed efficiency (FE) ofthe animal. By significantly increasing is preferably meant that thedose is preferably effective at P<0.05 which is a standard fordemonstrating a beneficial effect.

The peritoneum is the serous membrane lining of the abdominal walls(parietal peritoneum) and investing the viscera (visceral peritoneum).The parietal peritoneum is the membrane which lines the abdominal andpelvic walls and the undersurface of the diaphragm. The visceralperitoneum is the membrane reflected at various places over the viscera,forming a complete covering for the stomach, spleen, liver, ascendingportion of the duodenum, jejunum, ileum, transverse colon, sigmoidflexure, upper end of the rectum, uterus, and ovaries; it also partiallycovers the descending and transverse portions of the duodenum, thececum, ascending and descending colon, the middle part of the rectum,the posterior wall of the bladder, and the upper portion of the vagina.The peritoneum serves to hold the viscera in position by folds, some ofwhich form the mesenteries, which connect portions of the intestine withthe posterior abdominal wall; others, the omenta, folds attached to thestomach, and still others, the ligaments of the liver, spleen, stomach,kidneys, bladder, and uterus. The space between the parietal andvisceral peritoneums is the Peritoneal Cavity, which consists of thePelvic Peritoneal Cavity below and General Peritoneal Cavity above. TheGeneral Peritoneal Cavity communicates by the Foramen of Winslow withthe Cavity of the Great Omentum, which is also known as the LesserPeritoneal Cavity. As used herein, intraperitoneal cavity includes anyof the Pelvic Peritoneal Cavity, the General Peritoneal Cavity, and theLesser Peritoneal Cavity. More preferably, the implant is inserted intothe Lesser Peritoneal Cavity.

It has been established that access to the peritoneal cavity is bestgained by inserting a trocar through the left paralumbar fossa.Initially, it was thought that insertion through the right paralumbarfossa would be the preferred side, as the rumen is positioned adjacentto the left paralumbar fossa. However, it was determined that theposition of the kidneys and associated kidney are asymmetricallydistributed toward the right side of the body and interfere with trocaraccess to the peritoneal cavity. For this reason access to theperitoneal cavity is more easily accomplished through the leftparalumbar fossa.

The implantation is preferably accomplished using a two step procedure.In the first step, a vertical incision is made substantially through thehide alone of the left paralumbar fossa. The incision is verticalrelative to the ground and preferably less than 25 mm or 20 mm inlength. In the second step, a sterile non-toxic plastic tube having, forexample, a 30 bevel at the tip, optionally double-beveled, and providinga substantially-non-incising puncturing tip, is inserted through theincision and into the peritoneum. Sterile implants are insertedtherethrough and the tube is removed and the wound permitted to close.

The bST is intraperitoneally released since it has been observed thatsubcutaneous daily injections or prolonged non-intraperitoneal releasecan result in a decrease or in a nonsignificant change in dressingpercentage and have not resulted in significant increases in dressingpercentage and carcass weight.

Generally, it has been found that a practical minimum rate of releasefor observing significant changes in body weight or carcass weight oraverage daily gain or feed efficiency is about 3 mg/d bST and that aboveabout 14 mg/d bST, there is little additional improvement. Foradvantageous results, the intraperitoneal daily release is maintainedpreferably in the range of about 3 mg/d to about 14 mg/d. However,higher dosages can also be employed. More preferably the intraperitonealdaily release is maintained in the range of about 6 or 9 to about 12mg/d.

The release is preferably continuous since daily injections or biweeklyinjections can cause a reduction in dressing percentage. See, e.g.,Mosley et al., op. cit., and Wright et al., op. cit. However, apulsatile intraperitoneal release enhancing dressing percent issuitable, for example, a pulsatile release 6, 12 or more times per dayso that noncarcass growth is not unduly stimulated.

The preferably continuous release can be zero-order or non-zero orderprovided that the release threshold is preferably maintained in therange of above about 3 mg/d to about 14 mg/d, more preferably in therange of about 9 to about 12 mg/day that is, provided that the rate ofrelease does not fall below a value in these ranges during substantiallythe entire period of treatment. Preferably, also, the rate of releasedoes not exceed values of these ranges since higher dosages of bST whichare not maintained over the long term may favor increase in weight ofnon-carcass organs and such higher dosages may result if a prolongedcontinuous intraperitoneal release above the minimum is to be achievedusing a non-zero release implant.

bST is released at a substantially zero-order rate of release when therate of release is substantially independent of the amount of bSTremaining in the implant. It is preferred that the release besubstantially zero-order. Thus, for example, a constant rate of releaseis zero-order. Such a rate of release can be accomplished by an osmoticimplant such as described in Supplemental Exemplary Embodiment A.

Preferably the bST administration is effected by such an implantabledevice capable of delivering the desired dose of bST intraperitoneallyfor a prolonged period of time. Preferably, as indicated, the osmoticimplant is such as is described in Supplemental Exemplary Embodiment A.Other methods of achieving a substantially zero-order rate of releasecan also be used, for example, a pellet of bST having an approximatelyconstant-area release surface, or using other techniques known to thoseskilled in the art.

In the prior art, bST daily injection produced serum bST levels thatwere 400 to 700% higher than baseline for the first four hourspost-injection and returned to baseline about 12 hours after injection(Enright et al., 1990 and Early et al., 1990a); whereas continuous bSTdelivery from a pellet has been found to produce about a 100% increasein serum bST in Holstein heifers and no detectable increase in serum bSTin cross-bred steers. These data support a hypothesis, which should notbe considered to limit the invention, that a less-variablemore-continuous rate of delivery of bST in steers may reduce thedisproportionate growth of non-carcass components by establishing aneffective blood level for promoting growth of the carcass componentsthat does not exaggerate the growth of viscera and other non-carcasscomponents. Wagner et al., 1988, for example, used continuous deliveryof bST in an oil based system at a dose of about 70 mg/d and showed asignificant reduction in dressing percent. This might indicate thatviscera and other non-carcass components have a broader bSTdose-response window than components of the carcass. Concomitantly, thedose used by Wagner et al., 1988 was far in excess of that described aspreferred herein. In a companion study Wagner et al., 1988, showed thata 960 mg dose administered about every two weeks produced about a38-fold (3770% increase) in serum bST levels, when examined twelve dayspost injection of the second 960 mg dose. Such blood level changes inbST are in far excess of those required to stimulate carcass growth insteers, but potentially within the dose response of tissues associatedwith the non-carcass component. Accordingly, a controlled release of bSTwithin the window for increasing dressing percentage is preferred.

In Example B4 below, intraperitoneal bST osmotic implants in feedlotcattle increased dressing percent from 61.8% for the controls up to 62.4to 62.8% for bST treated animals. Possible explanations for this effectincluded 1) presence of performance enhancers (e.g., an estrogenicagent) and 2) the mode of delivery (zero-order intraperitonealdelivery). In Example B3 below, the synergistic effect of an estrogenicagent and intraperitoneal zero-order delivery of bST is demonstrated.Neither product alone caused a significant increase in dressing percent,but in combination-treated cattle there was a significant increase indressing percent.

In a study in which cattle received an estrogenic agent andintraperitoneal bST pellets, dressing percent was not significantlyaffected by treatment. However, as noted above, Wagner et al., 1988 hadtested a combination of an estrogenic agent and bST delivered on acontinuous basis, but had found that dressing percent still dropped from63.0% to 61.4%. It is possible that Wagner et al.'s failure todemonstrate a bST/estrogen-induced improvement in dressing percent wasdue to 1) the excessive bST dose (70 mg/d) and/or 2) poorly controlledbST delivery (a 960 mg 28-day dairy product injected every 14 days).Thus, the enhancement of dressing percent with an estrogenic agent andintraperitoneal bST zero-order delivery can be considered due to factorsincluding, 1) the synergistic effects of bST and the estrogenic agent,2) the effect of substantially zero-order osmotic bST delivery and 3)the effect of intraperitoneal delivery compared to subcutaneous deliveryof bST.

Most preferably, the implant is such as described in SupplementalExemplary Embodiment A attached hereto and incorporated by reference.Such implants may contain about 800 mg bST and release bST at a nominalrate of about 6 to 7 mg/d. Two or more implants can be used concurrentlyto achieve a desired rate of release, for example, about 10 mg/d to 12mg/d.

The implant, preferably providing a substantially constant release, isimplanted in the intraperitoneal cavity of the bovine being treated.Implanting in the intraperitoneal cavity facilitates recovery of theimplant with the non-carcass components of the bovine followingslaughter. In addition, the combination of intraperitoneal implant andsubstantially constant release has been found advantageous infacilitating a significant increase in dressing percent and carcassweight in bST-treated cattle.

Implantation is preferably accomplished via the left paralumbar fossasince this has been found, as indicated above, to facilitateimplantation. The left paralumbar fossa is a generally triangular areaon the bovine between the hip bone and the last rib and below the loinarea on the left side. Tissue and hide depth here is about 0.5 to 2.0",but trocars used for implantation are generally on the order of 1 to 5inches. The insertion depth of the trocar needs to be greater than theactual thickness of the paralumbar region due to stretching of theperitoneal lining. The only internal organs presenting a risk of injuryis the rumen. Damage to the rumen can be eliminated or reduced byadministering the implant to fasting or feed restricted animals. Othermethods of intraperitoneal administration may also be used.

bST is released intraperitoneally concurrently with administration of aneffective dose of an estrogenic agent. The estrogenic agent can beadministered either subcutaneously or intraperitoneally.

Any estrogenic substance may be used as the estrogenic agent. Anestrogenic substance is one which when administered to a normal femaleanimal will cause growth of the uterus and teats. However, onlyestrogenic substances which are suitable for administration to foodanimals can be put into actual use.

In actual use, the acceptable estrogens for food-producing animals areestrone and estradiol steroids such as 17-beta estradiol, estradiolbenzoate, ethinylestradiol, etc. or non-steroidal compounds withestrogenic activity, such as diethylstilbesterol, hexestrol, dianestrol,zeranol, etc., and derivatives of these substances. The simple esters,such as the C1-C6 alkanoates, and the benzoates, formed on one or two ofthe available hydroxy groups of estradiol and zeranol, or on the onehydroxy group of estrone are useful estrogenic substances. For example,estradiol benzoate, estradiol dipropionate, estrone acetate, zeranolhexanoate, zeranol dibutyrate, 17-beta-estradiol,17-beta-ethinyl-estradiol, can be used.

Other components which do not interfere with the desired estrogeneffect, such as progesterone, cholesterol, and other binding agents, andadditives may also be present.

Broadly the estrogen can be released in the range of about 5 ug/d to 500ug/d or even higher. Preferably the estrogen is released in the range ofabout 15 to about 60 ug/d. Generally, the dose of estrogenic agent canadvantageously be the same as that used when the estrogenic agent isadministered as an anabolic agent to cattle in the finishing stage ofgrowth to significantly increase body weight (BW) or carcass weight(CW). When the estrogenic agent is released from an intraperitonealosmotic pump, the effective dose may be even lower, for example, in therange of 15 to 30 ug/d.

As indicated, the estrogenic agent is delivered concurrently with theintraperitoneal release of bST, The administration of the estrogenicagent can be by pellets or other means such as are well-known in theart. Preferably, the estrogenic agent is delivered intraperitoneally inthe bovine using an osmotic pump, for example, the osmotic pump employedfor the bST or another separate osmotic pump containing the estrogenicagent in a suitable excipient.

Preferably, the estrogenic agent is released in the bovine for a periodof time generally concurrent with the period of bST delivery. However,treatment with an estrogenic agent prior to and concurrent with initialbST treatment has also been found effective.

Preferably the bST and/or estrogenic agent implant is implanted into theanimals at the beginning of the finishing stage of growth. However,either the estrogenic source or the bST implant or both may also beimplanted earlier and either provide a delayed initiation of bST releaseor a longer period of release.

The intraperitoneal bST release is provided preferably during the entireperiod of the finishing stage of growth and is continued substantiallyuntil the time for slaughter of the animals. It has been previouslyfound that the benefits of bST treatment may be adversely affected bydiscontinuation of bST. Hence, it is preferred that bST treatmentscontinue at least until a time when the beneficial effects of concurrentbST and estrogen treatment will persist at slaughter, for example, untilabout two weeks before slaughter and most preferably that bST release beongoing at slaughter.

The period of time during which an effective rate of intraperitonealrelease must be maintained can be any period effective for significantlyincreasing dressing percentage and carcass weight in finishing cattlereceiving an estrogenic agent. Currently, it is believed that a minimumof about 6 or even about 9-12 weeks are required. The period of bSTrelease is preferably at least for about 12 weeks prior to slaughter andmore preferably about 18 or more weeks prior to slaughter. Overall, theperiod of bST treatment can be from about 6 to about 24 or 30 weeks orlonger preceding slaughter of the beef cattle.

To obtain full benefit of the intraperitoneal release of bST, it ispreferred that the bovines be on a supplemented diet, that is, on a dietthat contains more protein or carbohydrate or fat or combinations ofthese than is found in hay or pasturage.

EXAMPLE B1 Weekly Subcutaneously Administered Pellets

A study was undertaken to determine the effect of 40 or 80 mg A-bSTpellets administered subcutaneously weekly during a 84-day beef cattlestudy on 1) growth, 2) feed efficiency and 3) carcass composition.

One hundred eighty Angus X Hereford beef steers weighing approximately350 kg (770 lbs) were used. Stocking density was 5 animals per pen. Thetrial consisted of 180 steers with replicates of 12 pens (60 animals)per treatment group (control, 40 mg bST/wk, and 80 mg bST/wk). The studylasted 84 days (12 weeks) exclusive of the pretreatment period. The dietfor all animals, on a dry matter basis, contained 16% crude protein("P"). Potable water was available ad libitum. Pens were randomlydistributed among treatments:

    ______________________________________                                               Treatment                                                              Trial  Group      Pens   Animals Description                                  ______________________________________                                        1      1          12     60      Control                                      1      2          12     60      40 mg/wk A-bST                                                                Pellets                                      1      3          12     60      80 mg/wk A-bST                                                                Pellets                                      ______________________________________                                    

The animals were slaughtered for carcass analysis. The results are shownon the following Table:

                  TABLE                                                           ______________________________________                                        TREATMENT                                                                                             40 mg/wk  80 mg/wk                                    Parameters      Control bST Pellets                                                                             bST Pellets                                 ______________________________________                                        Initial Body Wt (kg)                                                                          390.3   390.3     390.3                                       Final Body Wt (kg)                                                                            499.5.sup.a                                                                           495.0.sup.a                                                                             510.4.sup.b                                 Carcass Wt. (kg)                                                                              308.3   304.3     312.2                                       Dressing Percent (%)                                                                           61.7    61.5      61.2                                       Carcass Gain Response %)                                                                      --      No Gain    39%                                        Non-Carcass Gain Response (%)                                                                 --      No Gain    61%                                        ______________________________________                                         .sup.a,b different superscripts indicate that numbers in a row are            significantly different (p <.05).                                        

It was observed that neither dressing percentage nor carcass weight weresignificantly increased. Further, at the higher dosage, it was observedthat most of the increase in body weight due to bST treatment wasallocated to the non-carcass components.

EXAMPLE B2 Weekly Subcutaneous Intraperitoneal Pellets

A study was undertaken to determine whether the effect of 80 mg A-bSTpellets during an 84-day beef cattle study was comparable whenadministered subcutaneously and intraperitoneally.

Two hundred seventy Angus X Hereford beef steers weighing approximately350 kg (770 lbs) were bought and divided into three study groups.Stocking density was 5 animals per pen. Each study group consisted ofreplicates of 6 pens (30 animals) per treatment group (control, 40mgbST/wk subcutaneous pellet, and 80 mgbST/wk intraperitoneal pellet).The study lasted 84 days exclusive of the pretreatment period. The dietfor all animals, on a dry matter basis, contained 16% crude protein.Potable water was available ad libitum. Pens were randomly distributedamong the treatments:

    ______________________________________                                        Trial                                                                              Treatment  Pens   Animals Description                                    ______________________________________                                        2    1          12     30      Control                                        2    2          12     30      80 mg/wk A-bST                                                                Subcutaneous (SQ) Pellet                       2    3          12     30      80 mg/wk A-bST (IP)                                                           Intraperitoneal Pellet                         3    1          12     30      Control                                        3    2          12     30      80 mg/wk bST SQ Pellet                         3    3          12     30      80 mg/wk bST IP Pellet                         4    1          12     30      Control                                        4    2          12     30      80 mg/wk A-bST SQ Pellet                       4    3          12     30      80 mg/wk A-bST IP Pellet                       ______________________________________                                    

The animals were slaughtered for carcass analysis. The results are shownin the following Tables:

                  TABLE                                                           ______________________________________                                        TREATMENT                                                                                               80 mg/wk  80 mg/wk                                                            SQbST     IPbST                                     Parameters      Control   Pellets   Pellets                                   ______________________________________                                        Initial Body Wt (kg)                                                                          395.1     395.0     397.7                                     Final Body Wt (kg)                                                                            493.7.sup.a                                                                             499.5.sup.a                                                                             507.8.sup.b                               Carcass Wt. (kg)                                                                              304.2.sup.a                                                                             304.2.sup.a                                                                             311.2.sup.b                               Dressing Percent (%)                                                                          61.6.sup.a                                                                               60.8.sup.b                                                                              61.2.sup.ab                              Carcass Gain Response (%)                                                                     --         0%        61%                                      Non-Carcass Gain Response (%)                                                                 --        100%       39%                                      ______________________________________                                         .sup.a,b different superscripts indicate that numbers in a row are            significantly different (p <.05).                                        

It can be seen that, while the dressing percentage ofsubcutaneously-treated cattle was significantly decreased relative tothe control, the dressing percentage of intraperitoneally-treated cattlewas not significantly changed relative to the control.

EXAMPLE B3 Combination of Intraperitoneal bST Osmotic Pump and EstrogenPellets

A study was undertaken to determine the effects of intraperitonealrelease of bST, of subcutaneous estrogen pellets, or of the combinedeffects of the two.

Two hundred fifty-six cross-bred large frame steers weighingapproximately 430 kg (966 lb) were assigned to a control group and threetreatment groups and implanted with intraperitoneal bST pumps or/andsubcutaneous estrogen pellets. The bST formulation used was a 35% Zn⁻bST load in a phosphate buffer, glycerol, and Tween-80. The w/w/w%proportions respectively were 48.38/48.38/0.24. The phosphate buffer was60:40 monobasic:dibasic sodium phosphate at 1.0M. The time of release ofboth bST and estrogen was 87 days prior to slaughter. The results areshown in the following Table.

                  TABLE                                                           ______________________________________                                        TREATMENT                                                                                                          12 mg/d                                                     12 mg/d   O bST/  bST//                                                       bST O     200 ug/d                                                                              200 ug/d                                 Parameters                                                                             Control   Estrogen  Estrogen                                                                              Estrogen                                 ______________________________________                                        Initial  430.3     430.3     430.3   430.3                                    Body Wt                                                                       (kg)                                                                          Final Body Wt                                                                          544.9.sup.a                                                                             552.2.sup.a                                                                             567.1.sup.b                                                                           576.4.sup.d                              (kg)                                                                          Carcass  334.2.sup.a                                                                             340.3.sup.b                                                                             349.3.sup.c                                                                           359.7.sup.d                              Wt (kg)                                                                       Dressing 61.3.sup.a                                                                               61.6.sup.a                                                                              61.6.sup.a                                                                            62.4.sup.b                              Percent                                                                       (%)                                                                           Carcass  N/A        84%       68%    112%                                     Gain                                                                          Response                                                                      (%)                                                                           Non-Carcass                                                                            N/A        16%       32%    -12%                                     Gain                                                                          Response                                                                      (%)                                                                           ______________________________________                                         .sup.a,b different superscripts indicate that number in a row are             significantly different (P >.05)                                         

These results indicated that a significant improvement in dressingpercentage and carcass weight were achieved by intraperitoneal osmoticpump release of bST concurrent with estrogen treatment.

EXAMPLE B4 Combination of Intraperitoneal bST Osmotic Pump and EstrogenPellet

A study was undertaken to determine performance of intraperitonealosmotic pumps in finishing cattle concurrently being administeredestrogen. Six hundred seventy-two cross-bred large frame cattle weighingapproximately 412 kg were bought and assigned to a control group and sixtreatment groups of 96 cattle each. The cattle were implanted withintraperitoneal osmotic pumps capable of delivering 6, 12, 15 or 18 mgbST per day during an 84-day period ending with slaughter. The cattlereceived subcutaneous estrogen pellets during a 1 26-day period endingwith slaughter. The estrogen release is estimated at about 200 ug/d. Theresults are shown in the following table:

                                      TABLE                                       __________________________________________________________________________    TREATMENT                                                                               30% bST Load                                                                           40% bST Load                                                                           45% bST Load                                      Parameters                                                                          Control                                                                           6 mg/d                                                                            12 mg/d                                                                            15 mg/d                                                                           6 mg/d                                                                             12 mg/d                                                                           18 mg/d                                       __________________________________________________________________________    Initial Body                                                                        411.9                                                                             411.9                                                                             411.9                                                                              411.9                                                                             411.9                                                                              411.9                                                                             411.9                                         Wt (kg)                                                                       Final Body                                                                          555.1.sup.a                                                                       565.6.sup.bc                                                                      568.7.sup.bc                                                                       569.6.sup.c                                                                       561.8.sup.b                                                                        563.5.sup.bc                                                                      566.5.sup.bc                                  Wt (kg)                                                                       Carcass Wt                                                                          343.0.sup.a                                                                       353.1.sup.bc                                                                      355.4.sup.cd                                                                       357.2.sup.d                                                                       350.8.sup.b                                                                        351.3.sup.b                                                                       353.8.sup.bcd                                 (kg)                                                                          Dressing                                                                            61.8.sup.a                                                                         62.4.sup.b                                                                        62.8.sup.b                                                                         62.4.sup.b                                                                        62.4.sup.b                                                                         62.4.sup.b                                                                        62.5.sup.b                                   Percent (%)                                                                   Carcass                                                                             --   96%                                                                              104%  86%                                                                              116%  99%                                                                               95%                                          Response                                                                      (%)                                                                           Non-  --   4% -9%   14%                                                                              -16%  1%  5%                                           Carcass                                                                       Response                                                                      (%)                                                                           __________________________________________________________________________     .sup.a,b different superscripts indicate that numbers in a row are            significantly different (p <.05).                                        

The results of Examples B3 and B4 indicate that concurrentintraperitoneal treatment of finishing beef cattle with intraperitonealbST and estradiol significantly increase dressing percentage and carcassweight and furthermore allocate most of the increased weight to thecarcass components.

What is claimed:
 1. A method of implanting large diameter objects in theintraperitoneal cavity of bovines which can be accomplished readily,without significant injury to the bovine, requires minimal care afterimplantation, and rapidly heals, comprising:providing a generallycylindrical large diameter object having an outside diameter in therange of about 8 to about 15 millimeters (mm); making an incision ofless than about 25 mm in length in the hide of the left paralumbar fossaof a bovine, the incision effective for passing a first portion of agenerally cylindrical tube which itself functions as a trocartherethrough which has a external diameter of less than about 25 mm andwhich has an internal diameter for passing the large diameter objecttherethrough, the incision having an orientation and length and depthsuch that gaping of the resulting wound substantially does not occurafter inserting the tube and the object therethrough and removing thetube therefrom; inserting into the incision said generally cylindricaltube, said generally cylindrical tube further having a non-hide-incisingtip effective for penetrating tissues underlying the incision, and forpuncturing the peritoneum, and having a length for extending through theincision, underlying tissues, and into the intraperitoneal cavity of thebovine; causing the tip of the tube to penetrate the underlying tissuesand to puncture the peritoneum and inserting the large diameter objecttherethrough into the intraperitoneal cavity of the bovine; and removingthe tube.
 2. The method of claim 1 wherein:the incision comprises avertical incision.
 3. The method of claim 1 wherein:the inserting stepis conducted at a time when the rumen is not distended significantlyinto a portion of the peritoneal cavity being targeted.
 4. The method ofclaim 1 wherein:the bovine is a bovine fasting or feed-restricted for 6to 24 hours prior to implantation.
 5. The method of claim 1 wherein:thebovine is a bovine fasting or feed-restricted for 10 to 18 hours priorto implantation.
 6. The method of claim 1 wherein:the opening of thehide is less than about 20 mm.
 7. The method of claim 1 wherein:theobject is an osmotic pump capable of delivering about 3 to about 14mg/day of bovine somatotropin for a period of greater than 9 weeks andoptionally containing an estrogenic agent.
 8. The method of claim 1wherein:the tube and its contents are sterilely packaged with the largediameter objects therein and sterility is maintained until immediatelyprior to the inserting step.
 9. The method of claim 1 wherein:thesterility of an outside portion of the tube which will extend from hideto peritoneal cavity is maintained by a sheath removable prior to use.10. The method of claim 1 wherein:the incision is substantially throughthe hide only.